In a previous blog, we discussed how SARS-CoV-2, the virus that causes coronavirus disease COVID-19, can cause a cytokine storm leading to inflammation and a hypercoagulable state, both processes that place a patient at high risk for stroke. Health care providers have witnessed a disproportionately greater incidence of infarction among COVID-19 patients compared with non-COVID-19 patients. Researchers are now investigating whether there is a link between COVID-19 and stroke risk.

In March of this year, Belani et al. (2020) evaluated this relationship through a retrospective case-control study, collecting data from six hospitals. The goals of the study were to determine whether infection with COVID-19 is associated with an increased incidence of stroke and to assess whether it is an independent risk factor for infarction when controlling for conventional vascular risk factors (Belani et al., 2020). A cohort consisting of 123 patients were included and patients with acute ischemic stroke (small- or large-vessel occlusions) were matched with patients without stroke (control group) by age, sex, and major vascular risk factors including hypertension, coronary artery disease, diabetes mellitus type 2, atrial fibrillation, congestive heart failure, dyslipidemia, current or former smoking status, evidence of prior stroke, and body mass index (overweight or obesity).

Belani et al. (2020) found 19 out of 41 patients (46.3%) with acute ischemic stroke were confirmed to have COVID-19 infection compared with 15 of 82 patients (18.3%) in the control group. After controlling for age, sex, and major vascular risk factors, they determined:

• COVID-19 was an independent risk factor for acute ischemic stroke.
• There is a significantly greater incidence of acute ischemic stroke in patients with COVID-19 infection compared to those without infection.
• COVID-19 infection is associated with increased morbidity and mortality above what had been previously documented from the infection.
• Patients with severe COVID-19 had a 3-fold higher incidence of cardiovascular disease than those with mild-to-moderate disease.

Infections, in general, may lead to systemic inflammation, platelet aggregation and hypercoagulability and many prior studies have linked recent infection with an increase in the short-term risk of ischemic stroke (Cowan et al., 2018). An analysis of 727 ischemic stroke cases conducted by Cowan et al. (2018) found 6.1% to have had an inpatient infection and 23.8% had an outpatient infection in the 90 days prior to the stroke event (Cowan et al., 2018). One of the more common infections preceding stroke events were pneumonia/respiratory infections (15%) (Cowan et al., 2018). Inpatient infection was a stronger stroke trigger compared with outpatient infections and stroke risk was highest immediately following an infection (Cowan et al., 2018).

Mao et al. (2020) found SARS-CoV-2 may infect the nervous system and skeletal muscle and that severe infection may cause further neurological damage, including acute cerebrovascular diseases and decreased consciousness. Based on their research, Avula et al. (2020) suspect that increased levels of c-reactive protein (CRP), a blood marker of inflammation, and D-dimer (indicator for coagulation), may play a role in the pathophysiology of stroke in COVID-19 patients. Additionally, COVID-19 patients are at an increased risk for medical complications such as atrial arrhythmias, myocardial infarction, heart failure, myocarditis, and venous thromboses, resulting in a higher susceptibility to acute ischemic events (Merkler et al., 2020).

Klok et al. (2020) evaluated the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in 184 patients with COVID-19 pneumonia admitted to the ICU. The cumulative incidence of the composite outcomes was 31% with PE being the most frequent complication (Klok et al., 2020). Age and coagulopathy (prothrombin time greater than 3 seconds or activated partial thromboplastin time greater than 5 seconds) were independent predictors of thrombotic complications (Klok et al., 2020).

The following strategies are recommended to reduce the incidence of acute ischemic stroke:

• Patients with COVID-19 should be evaluated early for acute neurological changes and for patients suspected of having a stroke, promptly initiate work-up to decrease morbidity and mortality (Belini et al., 2020).
• For COVID-19 patients admitted to the ICU, ensure pharmacologic thrombosis prophylaxis has been initiated (Klok et al., 2020).
• Patients who developed an inpatient infection may benefit from cardiovascular disease preventive therapies (antiplatelet agents and statin) (Cowan et al., 2018).

The mounting evidence supports a link between COVID-19 infection and the incidence of stroke. While clinical practice does not change significantly based on these findings, health care professionals should maintain a heightened awareness of this risk.

References
Avula, A., Nalleballe, K., Narula, N., Sapozhnikov, S., Dandu, V., Toom, S., Glaser, A., & Elsayegh, D. (2020). COVID-19 presenting as stroke. Brain, behavior, and immunity, 87, 115-119. https://doi.org/10.1016/j.bbi.2020.04.077

Belani, P., Schefflein, J., Kihira, S., Rigney, B., Delman, B.N., Mahmoudi, K., Mocca, J., Majidi, ., Yeckley, J., Arrarwal, A., Lefton, D., & Doshi, A.H. (2020). COVID-19 Is an Independent Risk Factor for Acute Ischemic Stroke. American Journal of Neuroradiology. https://doi.org/10.3174/ajnr.A6650  

Cowan, L.T., Lutsey, P.L., Pankow, J.S., Matsushita, K., Ishigami, J. & Lakshminarayan, K. (2018). Inpatient and outpatient infection as a trigger of cardiovascular disease: The ARIC study. Journal of the American Heart Association, 7(22), 1-15. https://doi.org/10.1161/JAHA.118.009683

Klok, F.A., Kruip, M.J., van der Meer, N.J.M., Arbous, M.S., Gommers, D.A.M.P.J, Kant, K.M., Kaptein, F.H.J., van Paassen, J., Stals, M.A.M., Huisman, M.V. & Endeman, H. (2020). Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research. https://doi.org/10.1016/j.thromres.2020.04.013 .

Mao, L., Jin, H., Wang, M., Hu, Y., Chen, S., He, Q., Chang, J., Hong, C., Zhou, Y., Wang, D., Miao, X., Li, Y. & Hu, B. (2020). Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurology. 77(6):683-690. https://doi.org/10.1001/jamaneurol.2020.1127

Zayet, S., Klopfenstein, T., Kovacs, R. Stancescu, S. & Hagenkotter, B. (2020). Acute Cerebral Stroke with Multiple Infarctions and COVID-19, France, 2020. Emerging Infectious Diseases. 26(9).  https://wwwnc.cdc.gov/eid/article/26/9/20-1791_article