COVID-19 related stroke in young individuals

Evidence is mounting on the diverse neurological presentations associated with COVID-19. In a Rapid Review in The Lancet Neurology, Mark Ellul and colleagues¹ nicely cover these findings, but we would like to emphasise the risk of associated stroke. As described in this Rapid Review, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be more likely to cause thrombotic vascular events, including stroke, than other coronavirus and seasonal infectious diseases. In fact, a 7·6-fold increase in the odds of stroke with COVID-19 compared with influenza was recently reported.² The reported incidence of cerebrovascular disease in patients testing positive for SARS-CoV-2 ranges from 1% to 6%, potentially equating to large numbers of individuals as the pandemic progresses in some countries.1, 3

The proposed mechanisms for these cerebrovascular events include a hypercoagulable state from systemic inflammation and cytokine storm;¹ postinfectious immune-mediated responses;¹ and direct viral-induced endotheliitis or endotheliopathy, potentially leading to angiopathic thrombosis, with viral particles having been isolated from the endothelium of various tissue, including brain tissue.4, 5 Multiple regions with high COVID-19 prevalence have reported stable or increased incidence of large vessel stroke and increased incidence of cryptogenic stroke (patients with no found typical cause of stroke), despite observing a decrease in mild stroke that is possibly secondary to quarantine and self-isolation.⁶ This quarantine effect is supported by a nationwide analysis in the USA of automated stroke imaging processing software showing decreased imaging evaluation for stroke during the pandemic.⁷ Our group observed that five patients younger than 50 years who tested positive for SARS-CoV-2, some with no vascular risk factors, were admitted with large vessel stroke to our hospitals during a 2-week period (March 23 to April 7, 2020) during the height of the pandemic in New York City (NY, USA).⁸ This was a 7-fold increase in the rate of large vessel stroke in young people compared with the previous year, and the patients had laboratory findings that suggested a hypercoagulable state, leading to the postulation that stroke was probably related to the presence of SARS-CoV-2 in these young patients.⁹

Since then, this observation of COVID-19 related stroke in young patients has been supported by additional data from other centres worldwide. The mean patient age in several thrombectomy case series of COVID-19 (mean age of 52·8 years in a series from New York City [NY, USA],¹⁰ mean age of 59·5 years in a series from Paris [France],¹¹ and mean age of 59·5 years in a combined series from New York City and Philadelphia [PA, USA]¹²) is younger than the typical population having this procedure. Furthermore, in patients presenting with large vessel stroke during the pandemic, data from the Mount Sinai Health System in New York City confirm that patients who tested positive for SARS-CoV-2 were significantly younger, with a mean age of 59 years (SD 13), than patients who tested negative for SARS-CoV-2, who had a mean age of 74 years (SD 17),¹³ mirroring the findings of the Paris group.¹¹ Patients with COVID-19 who had imaging confirmed stroke and were admitted to another large New York City medical centre were again found to be younger, with a mean age of 63 years (SD 17), than a control group of patients with stroke who tested negative for SARS-CoV-2 and had a mean age of 70 years (SD 18).³ A case-control analysis of acute stroke protocol imaging from late March to early April, 2020, across a large New York City health system showed that, after adjusting for age, sex, and vascular risk factors, SAS-CoV-2 positivity was independently associated with stroke.

Many reports have documented an increased thrombosis risk early in COVID-19 and coagulation abnormalities in D-dimer and fibrinogen can be found in patients with mild symptoms. There are many reports of early COVID-19 presenting with thrombotic events, which has led to the consensus to start anticoagulation therapy early in the COVID-19 disease course before any thrombotic event. There are reports in the literature specifically addressing macrothrombosis in the internal carotid artery in patients with mild respiratory symptoms of COVID-1914, 15 and stroke as a presenting symptom of the disease.¹² A multicentre series of 26 patients with COVID-19 and either ischaemic or haemorrhagic events reported that 27% were younger than 50 years.¹⁶ Additionally, the report stated that two of 15 patients with large vessel stroke were younger than 50 years and without previous stroke risk factors. In this study, consistent with other case series, patients with COVID-19 fare worse in terms of clinical outcomes than patients with stroke who do not have COVID-19.6, 12 This is probably related, in part, to the COVID-19 disease process.

In conclusion, data supporting an association between COVID-19 and stroke in young populations without typical vascular risk factors, at times with only mild respiratory symptoms, are increasing. Future prospective registries to study this association further, as well as studies of anticoagulation to prevent these potentially life devastating events, are underway.¹ We believe that, in otherwise healthy, young patients who present with stroke during the pandemic, the diagnosis of COVID-19 should be thoroughly investigated. Conversely, in patients with mild COVID-19 respiratory symptoms, a low threshold for investigation for stroke should be maintained if they present with new neurological symptoms.