MINIREVIEW: Cerebral ischemic stroke as a manifestation of COVID-19

Author of summary: Giulia Colombo, Reviewer: Alessio Silva

Cerebral ischemic stroke is relatively common in COVID-19 patients who are at risk of acute cerebrovascular disease and is associated with common biochemical markers of inflammation, hypercoagulopathy and organ failure. The pathogenesis is to be clarified but seems to be related to the sepsis-induced coagulopathy and the following disseminated intravascular coagulation. Treatment with low molecular weight heparin or tissue plasminogen activator seems to be beneficial, but also human recombinant soluble ACE2 could be an option.

A case series from Wuhan, China had been analyzed in a retrospective study for three categories of neurologic manifestations linked to COVID-19 involving the central nervous system (dizziness, headache, impaired consciousness, acute cerebrovascular disease, ataxia and seizure), the peripheral nervous system (taste impairment, smell impairment, vision impairment and nerve pain) and the skeletal muscle. Of 214 patients (mean age 52.7 ± 15.5 years; 40.7% men) with COVID-19, 88 (41.1%) presented with a severe respiratory infection and, overall,78 cases (36.4%) had neurologic manifestations, mainly early in the illness history. Severe patients were older than those with less severe symptoms, had more underlying disorders, especially hypertension, and showed reduced fever and cough. Moreover, these patients suffered from neurologic involvements more frequently, such as acute cerebrovascular diseases (5.7% vs 0.8%), impaired consciousness (14.8% vs 2.4%), and skeletal muscle injury (19.3% vs 4.8%). These patients presented increased median levels of C-reactive protein, D-dimer, creatine kinase, lactate dehydrogenase, blood urea nitrogen and serum ferritin. Some were also positive for antiphospholipid antibodies, like anticardiolipin IgM.

Interestingly, in Western countries, an increasing body of evidence stresses the importance of cerebral ischemic stroke in COVID-19 epidemiology. In fact, many severe stroke cases have been linked to COVID-19, also with unusual characteristics:

• A 66-year-old French patient developed an acute ischemic stroke early after the onset of COVID-19 respiratory symptoms, complicating the large floating thrombus within the common carotid artery. Non-COVID-19 stroke patients rarely develop intraluminal floating thrombi in that region, which usually occur on ulcerated or stenotic plaques.
• Six patients of an English cohort presented large vessel occlusion, three had multiterritory infarcts, two had concurrent venous thromboembolism, and, in two, strokes occurred despite therapeutic anticoagulation.
• In a Turkish case-report, four patients with non-severe COVID-19 were reported to be simultaneously accompanied by neurological involvement of acute ischemic stroke.
• Five cases of large-vessel stroke in New York patients younger than 50 years illustrate that elders are not the only ones at risk.
• Severe coagulopathy in a patient from New Jersey with COVID-19 pneumonia caused multifocal thromboembolic disease involving the pulmonary, cerebral and renal circulations.

To date, it’s known that the clinical course of COVID-19 is most severe in old men who are subject to risk factors for stroke and with comorbidities such as hypertension, diabetes, heart disease and obesity. Moreover, an emerging hallmark of severe COVID-19 is a coagulopathy that has been termed sepsis-induced coagulopathy (SIC) with high D-dimer levels and elevated fibrinogen. SIC is a precursor state to disseminated intravascular coagulation(DIC) associated with elevated prothrombin time (PT), elevated D-dimer, and thrombocytopenia but without hypofibrinogenemia. SIC is related to an infection-induced systemic inflammatory response with endothelial dysfunction and microthrombosis with organ failure and usually no bleeding. So, patients with severe COVID-19 may be at risk of thrombogenesis and cerebral ischemia due to both a biochemical hypercoagulable state and direct vascular endothelial injury, since ACE2 is physiologically expressed by the endothelium.

Some patients with elevated D-dimer or SIC score had lower mortality when treated with heparin (mostly low molecular weight, LMWH) compared with those not treated; others reported improvement in respiratory parameters with the use of tissue plasminogen activator. However, early therapeutic anticoagulation with LMWH must be balanced against the risk of intracranial haemorrhage, including the haemorrhagic transformation of an acute infarct. For a more targeted COVID-19 therapy, one promising treatment is the administration of exogenous human recombinant soluble ACE2 (hrsACE2), which inhibits SARS-CoV-2 infections in engineered human blood vessel organoids and is now entering a clinical trial. hrsACE2 may work primarily in two ways: acting as a decoy by competing with the SARS spike protein for binding to lung and endothelial endogenous ACE2, thus to reduce infection of host cells; or by preventing the ACE2 depletion by the SARS- CoV-2 virus. The latter is crucial as ACE2 is a key part of the renin-angiotensin system, counterbalancing the angiotensin-converting enzyme 1 and angiotensin II, which is proinflammatory, vasoconstrictive and promotes organ damage.

In conclusion, given that timely assessment and hyperacute treatment is the key to minimize mortality and morbidity of patients with acute stroke, clinicians should be aware of the fact that COVID-19 patients can present with cerebrovascular accidents also as first relevant symptoms, and should be provided with appropriate personal protective equipment when in contact with any suspected patients. A challenge with acute stroke patients with COVID-19 is the inability to effectively communicate due to speech problems, altered mental status, inadequate clinical history (because of the limitations on visitors by hospital policies), etc. So, a dedicated neurology hot-spot along with a mobile CT unit for COVID-19 patients with stroke-like symptoms could be beneficial.

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