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Sharp Increase in Large-Vessel Stroke Risk Seen In Young, Healthy COVID-19 Patients

Article In Brief

Stroke neurologists at major medical centers reported an increased incidence of serious large vessel strokes in young COVID-19 patients. Not all the experts agree on the reasons why.

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Dr. Laura K. Stein, in personal protective gear, worked 12 straight 12-hour days in the emergency department at Mount Sinai Hospital.

A sharp increase in the incidence of serious large-vessel stroke among COVID-19 patients under age 50 has been reported by the largest medical system in New York City.

The report, in a letter to the editor of the New England Journal of Medicine published on April 28, described a two-week period in which five patients between the ages of 33 and 49 presented to the Mount Sinai Health System with new-onset symptoms of large vessel ischemic stroke. (None had serious symptoms of COVID-19, which was diagnosed only upon testing.) Their mean score at presentation on the NIH Stroke Scale was 17, which is consistent with a severe stroke. By comparison, the two-week average for such cases at Mount Sinai during the previous year was just 0.73 patients, according to the letter. Thus, the five cases between March 23 and April 7 represented a seven-fold increase over the usual rate.

Outcomes have been serious, with two discharged to a rehabilitation facility, one still in the stroke unit, and only one having returned home. The remaining patient, described in the paper as experiencing multi-organ failure, has since died. The poorer-than-average outcomes were attributed in part to the patients' delay in seeking medical care. The youngest, a female, presented at the hospital 28 hours after symptoms began, due to fear of COVID-19. Another presented 16 hours after symptom onset. Two presented at eight hours. The remaining patient presented after just two hours.

Some stroke neurologists at other hospitals around the country told Neurology Today they are seeing a similar trend, consistent with an increased risk of clots forming in other organ systems; they are now recommending that all patients with COVID-19 be treated with heparin or other therapy as a preventive measure.

Not all stroke neurologists, however, are convinced that the trend is real. Rather than an increase, some say they are seeing a sharp decline in strokes generally, especially mild strokes or transient ischemic attacks, in keeping with a broad decline in emergency department visits of all kinds other than those involving COVID-19. Even coauthors of the new report agreed that it's too early to be sure what the true link is between COVID-19 and stroke.

“We think there's a connection—we can't be certain, but it does seem to be real,” said Stanley Tuhrim, MD, professor of neurology and director of the division of vascular neurology at Mount Sinai Hospital. “And from speaking with colleagues around the country, I don't think it's an experience unique to Mount Sinai or even to New York City.”

Another report, now under review, involves a dozen stroke patients who were COVID-19 positive and treated at Thomas Jefferson University Hospitals in Philadelphia between March 20 and April 10.

“These are all preliminary results,” said Pascal Jabbour, MD, professor and chief of the division of neurovascular and endovascular neurosurgery in the department of neurological surgery at the Sidney Kimmel Medical College at Thomas Jefferson University. “In general, you cannot draw conclusions from a small case series. But in pandemics like this, everything moves quickly. If we see something unusual, we need to investigate it and report it.”

Dr. Jabbour is now in the process of collaborating with other centers in the United States and Europe on a larger analysis of strokes in COVID-19 patients, he said.

NEJM Case

The case described in greatest detail in the New England Journal of Medicine series from Mount Sinai involved a previously healthy 33-year-old woman who presented to the hospital with an NIHSS score of 19. She had previously developed cough, headache, and chills lasting one week, and then had dysarthria with both numbness and weakness in the left arm and left leg, which progressed for 28 hours before she finally went to the hospital.

CT and CT angiography revealed “a partial infarction of the right middle cerebral artery, with a partially occlusive thrombus in the right carotid artery at the cervical bifurcation,” the letter stated. “Patchy ground-glass opacities in bilateral lung apices were seen on CT angiography, and testing to detect SARS-CoV-2 was positive. Antiplatelet therapy was initiated; it was subsequently switched to anticoagulation therapy. Stroke workup with echocardiography and magnetic resonance imaging of the head and neck did not reveal the source of the thrombus. Repeat CT angiography on hospital day 10 showed complete resolution of the thrombus, and the patient was discharged to a rehabilitation facility.”

The letter noted that a report from Wuhan, China, pre-printed in The Lancet, described the incidence of stroke among hospitalized COVID-19 patients at about 5 percent. Large-vessel stroke was also reported in association with the 2004 SARS-CoV-1 outbreak in Singapore.

In just the two weeks since the Mount Sinai letter was submitted to the New England Journal of Medicine, three additional cases of large-vessel stroke in young patients with COVID-19 have presented to the hospital there, according to the letter's first author and neurologist Thomas J. Oxley, MD, PhD, an instructor and director of innovation strategy for the department of neurosurgery at Mount Sinai.

“When young patients present with a large-vessel stroke, we would normally expect to see substantial risk factors,” he told Neurology Today. “Most of these patients did not have any.”

Two of the patients had no risk factors for stroke: a 44-year-old man had undiagnosed diabetes and a 49-year-old man had a mild prior stroke and diabetes. The person who died, a 39-year-old man, had hyperlipidemia and hypertension.

In addition to the five patients under age 50 described in the letter, close to 40 other patients, of all ages, both patients positive and negative for COVID-19, presented at Mount Sinai with large-vessel strokes during a recent three-week period, according to neurologists there.

“It's probably close to 45 patients in three weeks,” said Laura K. Stein, MD, an assistant professor of neurology who serves as an attending stroke neurologist at Mount Sinai Hospital. “A little over half were COVID positive. Many were young and likely don't have the same risk factor we typically see.”

Dr. Stein expressed concern that outcomes for COVID-19 patients appear to be worse than she would normally expect.

“We give them tPA and thrombectomy but then they sometimes develop really bad swelling of the brain and a catastrophic outcome,” she said. “It's too early to tell if that's real or just an impression, but it's a concern right now that we're not seeing the same outcomes.”

On the other hand, she has also seen healthy young people with COVID-19 present with a clot in large vessel, but one that does not fully occlude. “They are treated with full-dose anticoagulation, and when we repeat the CT angiogram, we see that the clot is gone. It's quite remarkable.”

To better understand what is going on, she said, “We're embarking on an ambitious effort to study what we're seeing more closely. We want to compare people with stroke and COVID-19 to stroke without COVID-19. We also want to understand the difference between people who have mild or incidental COVID-19 with stroke, and those who have really severe COVID and then suffer a stroke or other thrombotic event.”

Dr. Stein spoke on Saturday, April 25, after completing 12 days as the attending stroke neurologist at Mount Sinai Hospital.

“Twelve straight days,” she said. “It was exhausting, but exciting. This is why I went into medicine. We were getting in at 8 every morning; some days I didn't leave my office till 10:30 at night.”

Mechanisms and Treatments

A potential explanation for why strokes should be occurring in seemingly healthy young people was offered in a paper published ahead of print in the Lancet on April 21. Researchers based at University Hospital Zurich noted that the SARS-CoV-2 virus infects hosts via the angiotensin-converting enzyme 2 (ACE2) receptor, expressed not only in the lungs but also in the heart, kidney, intestine and endothelial cells. The Swiss researchers described three cases in which they observed direct viral infection of the endothelial cells and diffuse endothelial inflammation.

“COVID-19-endothelitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19,” the paper stated. “This hypothesis provides a rationale for therapies to stabilize the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins.”

Another possible mechanism behind the apparent increased risk of stroke was described by Dutch researchers in a paper published online on April 10 in the journal Thrombosis Research. In 184 ICU patients with proven COVID-19 pneumonia, a composite outcome of either symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism was seen in 31 percent, a figure they called “remarkably high.”

Figure

At the main campus weve seen about 2,000 patients with COVID-19. Were still collecting and analyzing our data, but it seems to be around the order of 2 percent of them having a stroke. If you consider these are very sick people with lots of inflammation, thats not actually very high.”—DR. BABAK NAVI

“Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU,” the paper concluded, “and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.”

As a result of such findings, Mount Sinai instituted a new protocol earlier this month to raise prophylactic doses of heparin in some COVID-19 patients to that usually given to dissolved clots, even before any such clots occur.

“We expect there's a problem either with the coagulation system or the endothelial lining of their vessels,” Dr. Tuhrim said. “If there's a large-vessel occlusion amendable to thrombectomy, we certainly do that. In addition, we are anticoagulating these people. The hospital has developed a protocol, a very complicated algorithm, but it boils down to using anticoagulant with Lovinox or one of the newer oral anticoagulants in patients we might not otherwise have treated.”

While many other hospitals around the world are following a similar strategy, Dr. Tuhrim cautioned: “It's too soon to tell whether the strategy being deployed worldwide will turn out to be beneficial. It's a question of balancing the potential benefit against the risk of increasing hemorrhage.”

Steven R. Levine, MD, FAAN, Distinguished Professor of Neurology and Emergency Medicine at SUNY Downstate Health Sciences University and chief of neurology at University Hospital of Brooklyn has proposed a clinical trial to compare the approaches.

“You've got every recipe in the book for preventing clotting right now,” Dr. Levine said. “Some are giving aspirin, some are giving low-dose tPA, some are giving subcutaneous heparin. I've proposed a clinical trial with a standardized protocol of two or three treatments and an interim analysis so we can eliminate the ones that aren't working and find the optimal antithrombotic or anticoagulant.”

Collateral Damage?

Whatever the cause of the increased risk of stroke associated with COVID-19, Dr. Jabbour at Thomas Jefferson said that both the presentation and outcome are often worse than in other strokes.

“Usually these COVID-19 patients present with more than one vessel that is blocked,” he said. “We also notice that the outcome of these patients isn't so good. In our series, the mortality was around 55 percent. Despite the fact that we are opening the vessels, they end up having another major stroke. Their blood keeps clotting so quickly.”

Aside from mechanisms directly mediated by SARS-CoV-2 virus, another factor at play is the delay in presentation seen at Mount Sinai and elsewhere.

“We see patients presenting late,” Dr. Jabour said. “If they come too late, we can't help them.”

Babak Navi, MD, associate professor of neurology and neuroscience at Weill Cornell Medicine, division chief of stroke and hospital neurology, and medical director of the Weill Cornell Stroke Center, said that he, too, has seen many strokes in people with COVID-19, but that most are older and already critically ill from the viral infection.

“There are some younger people who have had vascular events and also tested positive for COVID-19,” he said, “but that's pretty rare despite the recent interest in this area. We're in the middle of the epicenter. At the main campus we've seen about 2,000 patients with COVID-19. We're still collecting and analyzing our data, but it seems to be around the order of 2 percent of them having a stroke. If you consider these are very sick people with lots of inflammation, that's not actually very high.”

He agreed, however, that COVID-19 patients who do have a stroke tend to fare poorly.

“A lot of that has to do with respiratory failure and other end-organ problems,” he said. “In some cases, the strokes are the fatal event, but these are very sick people.”

Dr. Navi called for better-designed studies to determine the true risk and best strategies for preventing and treating strokes in COVID-19.

“I think we need high quality, rigorous studies that are well controlled,” he said. “Making strong statements based on small, single center case series without comparison groups is problematic. Case series are useful in raising the suspicion for a novel or unique association or risk factor, but they need to be validated in methodologically strong studies. We're not there yet.”

Ashutosh P. Jadhav, MD, PhD, associate professor of neurology at the University of Pittsburgh Medical Center, said that he is not seeing a rash of COVID-19 patients with stroke. In fact, the number of stroke admissions across a 45-hospital network in the area fell by about 30 percent in March compared to previous years, although the number of large-vessel occlusions was more or less flat.

“The way I interpret that is that we are not seeing the milder strokes, but the severe strokes are still coming in,” Dr. Jadhav said. The likely result, he said, is that people who could benefit from treatment to prevent a second stroke are not getting it.

“People are not coming in to get the medical attention they need, because they're afraid to interact with the health system,” Dr. Jadhav said. “I call it collateral damage. In our part of the country, that's more impactful than COVID-19 itself. It's probably hurting more people than COVID-19 will.”

Even in New York City, Dr. Navi agreed that patients' fear of going to the hospital is cause for concern.

“I actually think that's a more concerning phenomenon,” he said. “The people with TIA and minor stroke are in my experience more likely to not call 911 and seek medical attention. Those are people we could potentially intervene on with evidence-based proven strategies who now we often cannot because they present to the hospital too late.”

Link Up for More Information

• Oxley TJ, Mocco J, Majidi S, et al. Large vessel stroke as a presenting feature of COVID-19 in the young https://www.nejm.org/doi/full/10.1056/NEJMc2009787. New Engl J Med 2020; Epub 2020 Apr 28.
    • Li Y, Wang M, Zhou Y, et al. Acute cerebrovascular disease following COVID-19: A single center, retrospective, observational study https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3550025. Lancet 2020; Epub 2020 Mar 13.
      • Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19 https://www.sciencedirect.com/science/article/pii/S0049384820301201. Thromb Res 2020; Epub 2020 Apr 10.
        • Varga Z, Flammer AJ, Steiger P, et al. Endothelial cell infection and endotheliitis in COVID-19 https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30937-5/fulltext. Lancet 2020; Epub 2020 Apr 17.