COVID-19 and cerebrovascular diseases: a comprehensive overview

Abstract

Neurological manifestations are not uncommon during infection with the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A clear association has been reported between cerebrovascular disease and coronavirus disease 2019 (COVID-19). However, whether this association is causal or incidental is still unknown. In this narrative review, we sought to present the possible pathophysiological mechanisms linking COVID-19 and cerebrovascular disease, describe the stroke syndromes and their prognosis and discuss several clinical, radiological, and laboratory characteristics that may aid in the prompt recognition of cerebrovascular disease during COVID-19. A systematic literature search was conducted, and relevant information was abstracted. Angiotensin-converting enzyme-2 receptor dysregulation, uncontrollable immune reaction and inflammation, coagulopathy, COVID-19-associated cardiac injury with subsequent cardio-embolism, complications due to critical illness and prolonged hospitalization can all contribute as potential etiopathogenic mechanisms leading to diverse cerebrovascular clinical manifestations. Acute ischemic stroke, intracerebral hemorrhage, and cerebral venous sinus thrombosis have been described in case reports and cohorts of COVID-19 patients with a prevalence ranging between 0.5% and 5%. SARS-CoV-2-positive stroke patients have higher mortality rates, worse functional outcomes at discharge and longer duration of hospitalization as compared with SARS-CoV-2-negative stroke patients in different cohort studies. Specific demographic, clinical, laboratory and radiological characteristics may be used as 'red flags' to alarm clinicians in recognizing COVID-19-related stroke.

Keywords: COVID-19; SARS-CoV-2; cerebrovascular disease; stroke.

Figure 1.

Potential pathophysiological mechanisms underlying cerebrovascular involvement in COVID-19. SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) receptors, leading to the receptors’ inactivation. ACE2 dysregulation contributes to the post-ischemic inflammation cascade, resulting in decreased perfusion in the ischemic zone and the development of larger infarct volume in the case of ischemic stroke (IS). In addition, ACE2 dysfunction may subsequently cause hypertensive peaks and impairment of cerebrovascular endothelium, contributing to the pathogenesis of intracerebral hemorrhage (ICH). Virus-related cardiac injury, including myocardial ischemia and cardiac arrhythmias such as atrial fibrillation, may cause cardio-embolism and subsequently, IS. COVID-19-related hypercoagulability may determine in situ arterial thrombosis and IS. Another potential IS mechanism related to hypercoagulability is paradoxical emboli of generated venous thrombi through right-to-left shunts. Cerebral venous thrombosis may also be caused by hypercoagulability and in situ thrombosis. Furthermore, COVID-19-related coagulopathy may present as dysfunctional hemostasis and predispose to ICH, especially when therapeutic anticoagulation is administered. Cytokine storm-mediated endotheliitis and vasculitis of the CNS due to SARS-CoV-2 infection causes vessel remodeling, leading to vessel occlusion or injury and IS or ICH, respectively. Finally, a primarily immune-mediated critical illness during COVID-19, hypoxemia, and systemic hypotension may induce hypoxic/ischemic encephalopathy or cerebral microbleeds with or without leukoencephalopathy. CNS, central nervous system; COVID-19, coronavirus disease 2019; DVT, deep venous thrombosis; PE, pulmonary embolism; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

Imaging evaluation of a patient with acute proximal occlusion of the right middle cerebral artery during hospitalization for COVID-19. A 65-year-old man with a history of hypertension and diabetes mellitus presented with acute left-sided hemiplegia, dysarthria, neglect, and right-gaze deviation. He had minimal respiratory symptoms. Emergency brain CT and CTA scanning were performed. Acute proximal right middle cerebral artery (MCA) occlusion was demonstrated on CTA (panel A, arrow) with evolving right MCA infarction. Right MCA occlusion was also confirmed on CTA 3D reconstruction (panel B, dotted circle). At that time, D-dimer levels were 2.8 ng/ml (normal values <500 ng/ml). The patient was not eligible for either intravenous thrombolysis due to delayed presentation or mechanical thrombectomy due to an unfavorable perfusion profile. Brain MRI was subsequently performed, showing restricted diffusion in right MCA territory, confirmative of large right MCA infarct (panel C). SARS-CoV-2 infection was confirmed at day 9 of hospitalization. On the 3-month follow up, the patient had modified Rankin Scale score of 4 with persistent severe left hemiparesis. COVID-19, coronavirus disease 2019; CT, computed tomography; CTA, computed tomography angiography; MRI, magnetic resonance imaging; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 3.

Imaging evaluation of a COVID-19 patient with large, multi-lobular intracerebral hemorrhage. A 55-year-old woman with a history of diabetes mellitus and hypertension was quarantined at home due to SARS-CoV-2 infection with mild respiratory symptoms. At 12 days later, she deteriorated, presenting dyspnea and respiratory failure. She was admitted to the ICU for mechanical ventilation. On day 11 of hospitalization, she became apneic on the ventilator, with fixed, dilated pupils. An emergent brain CT scan was performed showing a large, left-sided intracerebral hemorrhage causing compression of the ipsilateral lateral ventricle and midline shift to the right (panel A). The hematoma had an irregular, multi-lobular shape (panel A and B). No hypertensive spike was confirmed. The patient expired 1 day after neurological worsening. COVID-19, coronavirus disease 2019; CT, computed tomography; ICU, intensive care unit; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 4.

Imaging evaluation of a COVID-19 patient with cerebral venous thrombosis. A 59-year-old woman presented with a thunderclap headache followed by a severe progressive headache. Her neurological examination revealed bilateral papilledema. In the brain CT scan, she had an ischemic occipital lesion (panel A). Brain MRV demonstrated lack of flow in the left transverse and sigmoid sinuses, confirming the diagnosis of cerebral venous sinus thrombosis (panel B). In addition, the patient reported she had a fever, cough, and sore throat 10 days before her neurological symptoms. Chest CT showed diffuse ground-glass opacification (panel C). A positive SARS-CoV2 PCR confirmed the diagnosis of COVID-19. COVID-19, coronavirus disease 2019; CT, computed tomography; MRV, magnetic resonance venography; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 5.

Imaging evaluation of a COVID-19 patient with multi-territorial ischemic infarcts. An 83-year-old man with a history of hypertension, diabetes, hyperlipidemia, and prior ischemic stroke with no residual symptoms, presented to the emergency department with seizure-like activity and acute respiratory failure, likely due to aspiration. Brain MRI was performed showing restricted diffusion in the territories of both the right middle cerebral artery (MCA; panel A) and the right posterior cerebral artery (PCA; panel B), indicating right MCA and PCA acute ischemic stroke. He was intubated in the emergency department for decreased level of consciousness, hypoxia, and airway protection and initially admitted to the medical ICU. On presentation and the day after presentation, nasopharyngeal swab tests were performed and were both negative for SARS-CoV-2. At 10 days after initial presentation, a third nasopharyngeal swab was performed and found positive, confirming SARS-CoV-2 infection. Despite initial hypoxia and multiorgan failure, the patient improved systematically and was eventually weaned off the ventilator after 1 month of ICU hospitalization. However, the neurological examination did not improve accordingly, and the patient did not fully regain his level of consciousness. For that reason, a brain MRI was repeated and disclosed acute left MCA (panel C and D) and additional right MCA (panel D) territory recurrent ischemic infarcts. The patient was finally discharged to a long-term nursing facility and expired approximately 2.5 months after his initial presentation. COVID-19, coronavirus disease 2019; ICU, intensive care unit; MRI, magnetic resonance imaging; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.