Over the course of the past two years, the accepted understanding of how COVID-19 spreads and functions has improved vastly, with preventative vaccines and therapeutic drugs enabling patients to be treated more effectively. However, the relationship between the virus and many other severe conditions, such as stroke, is still shrouded in uncertainty. Early data from stroke patients with COVID-19 were divisive and, while several studies have since attempted to build on this, many questions remain unanswered. Here, NeuroNews gathers European and US perspectives from two physicians spearheading global research efforts to elucidate the link between COVID-19 and stroke.
The first COVID-19 case in New York was confirmed on 1 March 2020. By the end of that month, cases in the city were in the tens of thousands and New York City had become the worst affected region anywhere in the USA. Amidst the widespread panic surrounding a virus about which so little was known at the time, researchers at Mount Sinai Health System moved quickly to alert the world to a concerning early observation at their centre—large vessel occlusion (LVO) stroke as a presenting feature of COVID-19 in younger patients.
Speaking to NeuroNews, Johanna Fifi (Mount Sinai Health System, New York, USA), one of the authors who published this preliminary finding from five patients (aged <50 years) in the New England Journal of Medicine (NEJM) in April 2020, notes that their report was far from being universally accepted at first. “When New York City became one of the centres of the pandemic, we had a huge spike in infections and we were able to see this pattern over the course of two weeks of these younger patients coming in with stroke, and it sparked some scepticism from other parts of the country, because they were not seeing that,” she says.
According to Fifi, many other US centres were in fact seeing a decline in strokes—something that is now thought to have been caused by significantly fewer stroke presentations, particularly in more minor cases. A recent population study from Alberta, Canada, published in the Canadian Medical Association Journal, found a marked decrease in the number of stroke admissions compared to pre-pandemic numbers, and concludes that this is unlikely to indicate true declines in stroke occurrence but more likely reflects “pandemic-related hospital avoidance”. An alternative explanation offered by Fifi is that people generally being less active, among other lockdown-related lifestyle changes, may have reduced the stroke rate in some populations, although more evidence is needed to confirm this.
“We saw an overall increase in young people with LVO stroke, because COVID-19 causes clots to form that block the large vessels in the head and neck, and this was affecting slightly younger people who do not normally have strokes,” Fifi continues. “Elsewhere in the USA, and in other countries, there were lower infection numbers, so they just were not seeing this group of younger patients coming in. Some people wrote editorials on this, and one in particular suggested we were being alarmist, but—once COVID-19 spread across the rest of the country—people were able to look at their numbers, and that pattern was confirmed in numerous other cities and by big collaborations as well.” The publication Fifi references here is a letter published in Neurosurgery in September 2020, entitled “Dismantling the Apocalypse Narrative: The Myth of the COVID-19 Stroke”, which concluded that “there is currently no evidence supporting COVID-19 as a risk factor for stroke, independently of sepsis”.
As Fifi points out, it did not take long for this early finding to be verified by other groups across “hundreds” of academic papers and a more comprehensive report was published by Fifi and colleagues in The Lancet Neurology in September 2020. It alludes to findings from several thrombectomy case series in COVID-19 patients, including at Rothschild Foundation Hospital (Paris, France), in which the mean patient age is “younger than the typical population having this procedure”, as well as a retrospective cohort study at NYU Langone Health (New York, USA) that found COVID-19 patients with imaging-confirmed stroke were seven years younger, on average, than those in a control group who tested negative for SARS-CoV-2.
Despite a relative wealth of evidence on this phenomenon during the first few months of the pandemic, however, research into this and other aspects of the COVID-19-stroke relationship has since slowed, according to Richard Perry (University College London Hospitals, London, UK). “Not as much progress has been made as we might have hoped,” he tells NeuroNews. “There was a flurry of publications in 2020 and early-2021, but remarkably little in the way of new, more long-term clinical data has emerged since then.” Perry also notes that the current literature in this space is “extremely patchy”. “I think, without a shadow of doubt, recruitment biases have been a major contributing factor in creating these huge inconsistencies, where—for example—one study says LVOs are more common and then another study says they are not,” he claims, adding that variations in the data seen between different countries are more likely to relate to the study populations or healthcare settings involved, as opposed to actual geographical discrepancies.
We saw an overall increase in young people with LVO stroke, because COVID-19 causes clots to form that block the large vessels in the head and neck, and this was affecting slightly younger people who do not normally have strokes.
Much like Fifi and her team at Mount Sinai in the USA, Perry has been at the forefront of efforts from within the UK to elucidate the link between COVID-19 and stroke. He was the lead investigator for the case-control SETICOS study, which collected data from 13 hospitals in England and Scotland in mid-2020. It included 86 patients with evidence of COVID-19 at the time of stroke onset, and compared them to 1,384 stroke patients admitted during the same timeframe who never had evidence of COVID-19. The vast majority of strokes in both patient groups were ischaemic, as opposed to haemorrhagic, in nature.
Findings from SETICOS were published in the Journal of Neurology, Neurosurgery and Psychiatry in November 2020. Presenting these findings at last year’s European Stroke Organisation Conference (ESOC 2021; 1–3 September, virtual), Perry said: “COVID-19 does appear to have a significant impact on stroke.” He reported that the proportion of ischaemic strokes was higher in the COVID-19 group and that, looking at those ischaemic strokes, COVID-19 cases were associated with a greater stroke severity on admission, a higher mortality rate during admission, and more severe disability on discharge. “There was also an association between COVID-19 and the finding of multiple LVOs on CT [computed tomography] angiography,” he added.
“The main thing that comes out very consistently is that, if you have COVID-19 at the time of your stroke, your outcome is worse—there is no doubt about that,” Perry continues. “One can argue about what mechanisms are behind this, but that is a very, very consistent finding across all of the studies.” This view is endorsed by Fifi, who adds that there are various large epidemiological studies showing that stroke in COVID-19 is different from other strokes, and the outcomes of COVID-19-related stroke are often worse than those seen in stroke patients without COVID-19 from the same patient cohorts. “This is also the case with other viruses, but it is increased with COVID-19—with a risk that is potentially seven times higher compared to influenza,” she states. “This is very well-accepted at this point, more than two years on from when it was first noted.”
Alarming trend or alarmist myth?
Discussing the “very famous” NEJM report from Mount Sinai on younger LVO stroke patients with COVID-19, Perry notes that his own stroke unit published a similar cases series of six patients around the same time—but believes such publications now serve as “a lesson in being very careful not to overinterpret small case series”. “We now have a better level of evidence, through cohort studies with proper COVID-19-negative controls, from which to draw conclusions,” he adds. “In our study [SETICOS], the age distribution of the COVID-19-positive and COVID-19-negative patients was identical, so it cannot be the case that patients who have COVID-19 at the onset of their stroke are a completely different population with a younger median age.
“I think that, among patients presenting to a stroke unit through the usual patient pathways, those with COVID-19 are not younger. There does seem to be a difference with regard to the frequency of LVOs, but this varies from one study to another, and it is not as straightforward as we perhaps thought it might be at the time of those early reports. Our study did not show any difference in the overall frequency of LVOs. We did find a significantly higher proportion of patients with multiple LVOs in our COVID-19 group, but I do not know whether that will be confirmed in other studies.”
Fast-forward to April 2021—a full year on from the publication of those initial case reports—and a review paper in Trends in Neurosciences, which Fifi was also the lead author for, can be seen to corroborate this more tentative viewpoint. Here, the researchers acknowledge limitations surrounding their previously reported experience, as well as noting that the high prevalence of COVID-19 in New York City at the time those studies were performed “raises the possibility that COVID-19 infection in the young stroke patients described previously may have been incidental”. They further state that, in elderly patients, the presence of diabetes, hypertension and many other traditional risk factors for stroke—even at differential rates between COVID-19 positive and negative cohorts—makes elucidating the exact role of COVID-19 in stroke pathogenesis difficult. “Further study of large cohorts is necessary to understand the extent to which COVID-19 infection precipitates stroke as well as the underlying pathogenesis,” they conclude.
The greater breadth of evidence both Fifi and Perry call for could be seen to have emerged in the early part of 2022, however. An international, multicentre study published in Neurosurgery in March—which claims to be the largest study on LVO stroke and COVID-19 to date—came to the conclusion that LVO stroke patients with COVID-19 were younger, and generally healthier, than those not infected with the virus. Conducted through a global collaboration led by Thomas Jefferson University (Philadelphia, USA), the retrospective analysis evaluated a total of 575 acute LVO patients across 50 comprehensive stroke centres. Some 194 of these patients had COVID-19, while 381 (a control group of LVO stroke patients who received a mechanical thrombectomy between January 2018 and December 2020) did not.
An examination of these data revealed that, on average, patients with COVID-19 were nearly 10 years younger than those without (mean age=62.5 vs 71.2 years), and the COVID-19 group also contained twice as many people under the age of 50 years. In general, those in the COVID-19 group had fewer cerebrovascular risk factors, and were more likely to experience unfavourable outcomes, with higher morbidity/mortality rates being observed compared to the non-COVID-19 group. The study’s corresponding author, Pascal Jabbour (Thomas Jefferson University, Philadelphia, USA), noted that “many neurosurgeons” saw that COVID-19-positive stroke patients were often younger, had multiple large vessels blocked, and frequently had worse outcomes than their usual patients, at the start of the pandemic, adding: “This international study confirms those early, alarming observations.”
Further evidence required
Perry has his reservations regarding studies like this that assess COVID-19-associated stroke against historical controls. “Such comparisons are flawed because of an unavoidable bias,” he says. “Patients with mild stroke stayed away from the hospital, certainly during the first phase of the pandemic. Thus, the average stroke is more severe in pandemic patients than pre-pandemic patients—regardless of their COVID-19 status. So, taken at face value, such studies will tend to show that COVID-19 causes more severe strokes even if, in fact, it does not.”
While he contests the evidence upon which COVID-19 has been linked to LVO stroke in younger, healthier patients, Perry feels that alternative studies, such as SETICOS, and analyses conducted by other US groups in New York and Chicago, as well as European teams in Paris and Madrid, offer more telling insight. He attributes this to their use of contemporaneous control groups. “These studies can tell us about the impact COVID-19 has on stroke,” he asserts.
Without a shadow of doubt, recruitment biases have been a major contributing factor in creating these huge inconsistencies, where—for example—one study says LVOs are more common and then another study says they are not.
“Strokes—whether ischaemic or haemorrhagic—appear to be much more severe in patients with COVID-19, with a higher mortality,” Perry adds, reaffirming data from the SETICOS study. He also notes that most of the existing information relates to ischaemic stroke, and that haemorrhagic stroke is a more difficult topic to study. “We have done a meta-analysis of existing published data, which shows that outcomes [in haemorrhagic strokes] are much worse,” he states. “However, the question of whether COVID-19 increases the risk of intracerebral haemorrhage is potentially confounded by intensive care unit-related treatments for severe COVID-19, which may increase that risk too.”
Perry is also quick to emphasise that the question of whether COVID-19 actually ‘causes’ stroke is a distinct matter, and one that is “very difficult” to assess. “There are hints that, in a small minority of patients with COVID-19 at the onset of their stroke, the stroke was ‘caused by’ the virus, but that is hard to prove,” he says. “There may be a small subgroup of patients whose strokes are caused by COVID-19-related mechanisms, and they may need a different treatment approach—particularly with regard to antithrombotic agents. This is perhaps the most important question of all for future research.”
Future research directions
On this front, Perry and Fifi are well-aligned. Both allude to the important role future research will play in elucidating the myriad of mechanisms by which COVID-19 may influence and/or cause stroke symptoms. “Funding to support basic investigations into the pathogenesis of stroke in COVID-19 would be helpful,” Fifi states. “And, the mechanisms by which COVID-19 induces thrombus formation are important to fully elucidate.” She also notes that these investigations could be even more complex, and will entail laboratory studies and further pathologic data to gain an improved understanding of the virus itself.
Similarly, Perry outlines five key areas that are among numerous factors thought to play a role in this relationship—mainly based on blood and cerebrospinal fluid tests in severe COVID-19 patients. These include coagulopathy, angiotensin-converting-enzyme (ACE)2 receptors, infection of endothelial cells/endotheliitis, inflammatory mechanisms like increased interleukin levels and platelet activation, and cardiac factors, such as myocardial injury or arrhythmias. “It would be lovely to have a simple story and be able to say it is just coagulopathy, or it is just ACE inhibition, but I am increasingly convinced that it will never be as simple as that,” Perry notes. “We have this plethora of mechanisms and they are all contributing to a certain degree in different situations—which means it is also going to be difficult to come up with a rational treatment strategy.”
Perry thinks large, dedicated trials, involving COVID-19 groups and non-COVID-19 control groups of stroke patients, are now key, and could yet help to establish which of these baseline variables are more predictive of poor outcomes. He notes that expanded data from SETICOS and other international collaborations will likely be vital on this front. Fifi claims that, in addition to being younger, patients who are COVID-19-positive at the time of their stroke also tend to be male, and part of an ethnic minority group, as per a Stroke case series from New York in 2020. Further research is required to tease out whether these discrepancies are a product of biological or socioeconomic factors, she adds.
While the underlying link between COVID-19 and stroke is yet to be fully unravelled, Perry and Fifi both believe increasing stock should be placed in optimising the treatment of COVID-19-positive patients too. Building on one of the concluding messages from her team’s 2021 Trends in Neurosciences paper, which was that “significant work remains to be done to better understand the pathogenesis of COVID-19-related stroke and for designing optimal primary and secondary prevention strategies”, Fifi asserts that “major funding” is required to move this area forward. “Some investigations regarding the initiation of anticoagulation or antiplatelet therapy in COVID-19 are ongoing, specific focus on the prevention of stroke—along with [other indications such as] heart attacks and deep venous thrombosis—are welcome, and the risks and benefits of medications like aspirin in mild COVID-19 need to be fully elucidated,” she concludes.
Perry states: “Personally, I do believe that there is a subgroup of patients whose stroke is truly caused by COVID-19-related coagulopathy, and I strongly suspect these patients should be anticoagulated rather than given antiplatelets.” He concedes, however, that this suspicion is not clearly supported by any existing datasets and, until the aforementioned patient group has been identified—possibly via widescale population studies—there is “no reason at all” to think patients with COVID-19-associated stroke should not receive procedures like intravenous thrombolysis or mechanical thrombectomy, in line with existing treatment criteria. Perry also feels the UK RECOVERY trial, which claims to be the world’s largest clinical study evaluating COVID-19 treatments, with more than 40,000 participants across 185 sites, could shed some much-needed light on an area that is still largely swathed in darkness.