‘Relatively Low’ Stroke Incidence in COVID-19, but More Are Cryptogenic

Patients diagnosed with COVID-19 have a “relatively low” rate of imaging-confirmed stroke—lower than seen in historical controls—but a far greater rate of cryptogenic stroke than that seen both historically and in a contemporary cohort not known to be infected, new observational data show. The findings speak to the complex interplay between disease mechanisms and patient behavior: hypercoagulability is emerging as a hallmark of this disease at the same time that patients, fearing infection, are not heading to hospital with acute symptoms.

As previously explored by TCTMD, COVID-19 appears to cause more strokes, especially in younger patients, and in some cases stroke is actually the presenting symptom of infection. On the other hand, hospital avoidance by patients experiencing acute cardiovascular problems, including myocardial infarction and stroke, has also proved to be a devastating consequence of stay-at-home orders.

“We were a little bit surprised by the low rate of ischemic stroke in patients with COVID-19,” Shadi Yaghi, MD (New York University School of Medicine, Brooklyn), told TCTMD. “Other reports suggested higher rates. . . . But other findings in our study were not very surprising because we were all taking care of those who had strokes in the setting of COVID, and we already have seen and have some anecdotal experience from the patients we saw in the hospital with ischemic stroke” who also tested positive for the virus.

For their study, published online this week ahead of print in Stroke, Yaghi and colleagues retrospectively included the 3,556 consecutive patients hospitalized for COVID-19 in their healthcare system between March 15 and April 19, 2020. In total, 32 patients (0.9%) had an ischemic stroke as proven by radiological imaging, with a median age of 62.5 years. Of these, 43.8% were initially hospitalized for their stroke and the remainder for COVID-19 symptoms. The median time from onset of COVID-19 symptoms to stroke identification was 10 days.

The study cohort had a higher rate of cryptogenic stroke (65.5%) as compared with contemporary controls (those hospitalized for stroke during the same period but without COVID-19; 30.4%; P = 0.003), as well as compared with historical controls (patients hospitalized for stroke between March 15 and April 19, 2019; 25.0%; P < 0.001).

Compared with contemporary controls, the study cohort had numerically higher National Institutes of Health Stroke Scale (NIHSS) scores (OR per point increase 1.14; 95% CI 0.99-1.31) and higher peak D-dimer levels (OR per 100 ng/mL increase 1.02; 95% CI 1.00-1.05). Also, after adjustment for age and NIHSS score, those with COVID-19 and stroke were more likely to die in the hospital than both contemporary (adjusted OR 64.87; 95% CI 4.44-987.28) and historical controls (adjusted HR 40.27; 95% CI 5.44-298.01).

Notably, only 70% of contemporary controls were screened for COVID-19, so it is possible that some may have been asymptomatic.

Unknowns and Clinical Implications

“Our study is important because it sheds light on the characteristics and potential mechanisms of stroke in patients with COVID-19 compared to controls, and I think it moves the field forward in trying to understand these mechanisms and hopefully trying to understand what is the best treatment to prevent stroke and thrombotic complications in patients with COVID-19,” Yaghi said.

Reasons for the lower observed rate of confirmed ischemic stroke in COVID-19 patients as compared with other series are unknown, the authors write, “but could possibly be related to differences in the patient population studied in our patient population as compared to the other studies, and other studies including hemorrhagic stroke and venous sinus thrombosis patients. In addition, the rate of ischemic stroke in our study may be an underestimate as the detection of ischemic stroke symptoms is challenging in those critically ill with COVID-19 infection who are intubated and sedated.”

The findings also show an initial increase of COVID-19 positive ischemic strokes, though this seems to have peaked and then decreased over the timeline of the pandemic, the authors add. “This finding may be related to the overall reduction in COVID-19 admissions, likely due to social distancing and stay at home orders.” It’s also possible that a therapeutic anticoagulation protocol, which was instituted at their institution beginning April 6, 2020, “may have led to a lower rate of thrombotic complications including ischemic stroke in hospitalized COVID-19 positive patients.”

Yaghi and colleagues note that the decrease in ischemic strokes observed during their study period in 2020 versus 2019 has been observed elsewhere and is possibly due to the fact that “patients with stroke and mild symptoms are staying at home and not presenting to the emergency department for stroke treatment.”

It is increasingly accepted that the hyperinflammatory state, cytokine storms, and hyperviscosity seen in a subset of COVID-19 patients leads to increased thrombotic complications, although how much this is driving stroke patterns is unclear. “During the first SARS outbreak in the early 2000s, postmortem studies demonstrated a florid vasculitis in multiple arterial beds, and it is not known whether this disease pattern occurs with severe acute respiratory syndrome CoV-2 coronavirus infection,” the investigators write.

The ongoing randomized PROTECT COVID study is testing whether giving anticoagulants to patients with evidence of a blood clotting abnormalities will reduce the risk of stroke and thrombotic events, and Yaghi encouraged clinicians to enroll patients if they meet the study inclusion criteria. “To be able to move the field forward and to answer this very important question, I think we need a randomized clinical trial,” he said.

In the meantime, Yaghi advised clinicians to be hypervigilant about stroke symptoms in patients with COVID-19. “Although it’s not common, I think we should be doing neurological exams when indicated in patients with COVID,” he said. “We've seen strokes, we've seen other neurological complications, so do neurological assessments when necessary and indicated on these patients to try and be able to diagnose and treat stroke when it happens.”