People hospitalized with COVID-19 and neurological problems including stroke and confusion, have a higher risk of dying than other COVID-19 patients, according to a study published online today by researchers at Montefiore Health System and Albert Einstein College of Medicine in the journal Neurology, the medical journal of the American Academy of Neurology.
These findings have the potential to identify and focus treatment efforts on individuals most at risk and could decrease COVID-19 deaths.
The study looked at data from 4,711 COVID-19 patients who were admitted to Montefiore during the six-week period between March 1, 2020 and April 16, 2020. Of those patients, 581 (12%) had neurological problems serious enough to warrant brain imaging. These individuals were compared with 1,743 non-neurological COVID-19 patients of similar age and disease severity who were admitted during the same period.
“This study is the first to show that the presence of neurological symptoms, particularly stroke and confused or altered thinking, may indicate a more serious course of illness, even when pulmonary problems aren’t severe,” said David Altschul, M.D., chief of the division of neurovascular surgery at Einstein and Montefiore and associate professor in the Leo M. Davidoff Department of Neurological Surgery and of radiology at Einstein. “Hospitals can use this knowledge to prioritize treatment and, hopefully, save more lives during this pandemic.”
Among people who underwent brain imaging, 55 were diagnosed with stroke and 258 people exhibited confusion or altered thinking ability. Individuals with stroke were twice as likely to die (49% mortality) compared with their matched controls (24% mortality) – a statistically significant difference.
People with confusion had a 40% mortality rate compared with 33% for their matched controls—also statistically significant.
More than half the stroke patients in the study did not have hypertension or other underlying risk factors for stroke. “This highly unusual finding agrees with other studies of people with COVID-19 in suggesting that infection with the novel coronavirus is itself a risk factor for stroke,” said Dr. Altschul, who is also surgical director of the Montefiore Comprehensive Center for Stroke Care, and the study co- author, along with Emad Eskandar, M.D., M.B.A., chair of neurological surgery at Einstein and Montefiore, professor in the Leo M. Davidoff Department of Neurological Surgery, the department of psychiatry and behavioral sciences, in the Dominick P. Purpura Department of Neuroscience at Einstein. Dr. Eskandar also holds the Jeffrey P. Bergstein Chair and the David B. Keidan Chair in Neurological Surgery.
The paper is titled “Neurologic Syndromes Predict Higher In-Hospital Mortality in COVID-19.”
Several findings from this study investigating stroke risk, characteristics, and outcomes among patients with COVID-19 deserve discussion (figure 4). Consistent with the main study hypothesis, the proportion of patients with COVID-19 experiencing a stroke was high relative to patients with other viral respiratory diseases.
In-hospital mortality was exceedingly high for patients with COVID-19 with strokes of any type and ischemic stroke. In-hospital mortality was higher for young patients with COVID-19 with stroke of any type than for those >70 years of age. However, this was not found among patients with ischemic stroke.
The presence of LVO was high across all ages but was not statistically significantly higher for the youngest age group. By applying unsupervised learning, we identified specific phenotypes of patients with COVID-19 with stroke, characterized by the interplay of older age, cardiovascular comorbid conditions, and severe COVID-19 respiratory symptoms, which were associated with increased risk of death. The severity of COVID-19 respiratory symptoms was the factor most strongly associated with stroke mortality.
We found that the occurrence of stroke among hospitalized patients with COVID-19 was relatively high (1.8%, 95% CI 0.9%–3.7%) compared to patients with other viral respiratory infections or even sepsis. We found similar results in the meta-analysis for ischemic stroke (1.6%, 95% CI 0.8%–2.8%).
The observed risk of stroke was double that reported in patients with SARS-CoV-1 (0.75%)23 or severe sepsis (0.78%).24 The risk of ischemic stroke was 8 times higher than that reported among hospitalized patients with influenza (0.2%).25 Although high, these numbers likely constitute an underestimate of the actual frequency of stroke among patients with COVID-19 because of missed stroke diagnoses in those who were not extubated after prolonged periods or did not survive mechanical ventilation.26
The lack of autopsies27 and restrictions on investigations related to safety recommendations28 or hospital policies may have contributed to further underestimation of the risk of stroke among hospitalized patients with COVID-19. Furthermore, the well-recognized drop in the number of patients with acute cerebrovascular symptoms seeking medical attention in the COVID-19 era also may have contributed to the underestimation of the frequency of stroke occurrence in this population.29
In-hospital mortality was remarkably high for the whole cohort (≈35%) and even higher (≈45%) after the exclusion of patients whose outcome was undetermined at the time their cases were reported (e.g., those who were still admitted). In-hospital mortality in this cohort of patients with COVID-19, which comprised mainly cases with ischemic stroke, was higher than recently reported in a cohort of patients with COVID-19 with acute ischemic stroke (27.6%).30
It was also higher than reported 30-day case fatality rates for ischemic stroke, ranging from 9% to 19%,31 or in-hospital mortality of patients with stroke admitted to intensive care units, ranging between 14.7% and 21.9%.32,33 It must be noted that the limited testing in several countries may have led to inflation of death rates.
The elevated incidence of potentially fatal thrombotic complications in patients with COVID-19 and stroke could have contributed to their increased risk of death. Indeed, we found that the combination of deep vein thrombosis and pulmonary embolism was frequent among patients with COVID-19 with stroke, affecting ≈11% and ≈13% of all strokes and ischemic strokes.
This number is >10 times higher than the reported incidence of pulmonary embolism within 30 days of ischemic stroke occurrence in a Canadian population-based study (0.78%).24 Pulmonary embolism also may explain paradoxical embolism in patients with COVID-19 with ischemic stroke, as recently documented in 2 COVID-19 cases showing a thrombus in transit through a patent foramen ovale.35,36
Patients <50 years of age with any stroke or ischemic stroke had the lowest prevalence of hypertension and atrial fibrillation compared to other age groups. Young patients with stroke of any type also had the lowest prevalence of coronary artery disease. Approximately 50% of patients <50 years of age experienced their strokes before the onset of COVID-19 respiratory symptoms, and this was significantly more frequent than in other age groups.
This finding may imply that, in the COVID-19 era, younger patients presenting to the emergency department with acute stroke would need to be tested for SARS-CoV-2 even in the absence of specific symptoms or regardless of having passed a COVID-19 screen.
The frequency of LVO was highest among young patients (68.8%). However, this difference was marginally significant (p = 0.049), and the unadjusted odds of young patients for presenting more frequently with an LVO than the rest of the cohort was nonsignificant (uOR 2.46, 95% CI 0.83–7.30, p = 0.10).
This may be due to the lack of adjustment, the study sample size, or publication bias. In addition, the nonsignificant differences in the proportion of patients presenting with LVO could be due to a consistently high prevalence of LVO across all age groups. Indeed, the observed overall 46.9% prevalence of LVO in the whole cohort of patients with ischemic stroke was almost twice as high as the 29.2% recently reported in a population-based study.37
Similarly, 68.8% of patients with ischemic stroke who were <50 years of age in our study had an LVO compared to 29.7% in the same population-based study.37 The high prevalence of LVO in the context of a low burden of comorbid conditions in young patients with COVID-19 with stroke strongly supports the role of hypercoagulability as a cause of arterial thrombosis in this age group.
This concept is further reinforced by the >4 times higher proportion of cases with elevated D-dimer in our cohort of patients with ischemic stroke (82.7%), particularly among young patients (90.0%), compared to the overall reported prevalence among patients with COVID-19 (20.4%).38
Furthermore, recent reports of free-floating thrombi in the carotid39 or aortic40,41 arteries of patients with COVID-19 without structural vessel wall abnormalities such as plaque ulceration, inflammation, or hemorrhage29,30 suggest that COVID-19–related hypercoagulability could cause arterial thrombosis and embolism in the absence of underlying arterial wall disease.
Only 3 of 11 (27%) young patients with an LVO received a mechanical thrombectomy. Considering that 50% of young patients with acute ischemic stroke had no COVID-19 respiratory symptoms before stroke onset, it is possible that some patients decided to stay home instead of seeking medical attention because of concerns of being exposed to SARS-CoV-2 in the emergency room.29
Patients with ischemic stroke who were <50 years of age showed the highest frequency of elevated cardiac troponin (80.0%, p = 0.046). Increased cardiac troponin is a marker of either acute or chronic myocardial injury42 and is strongly associated with the risk of stroke.43 In the general population, factors most consistently associated with chronic myocardial injury are vascular risk factors and cardiovascular comorbid conditions such as atrial fibrillation and coronary artery disease.42
In patients with stroke, elevated cardiac troponin is explained by either chronic (secondary to baseline underlying heart disease) or acute (neurogenically mediated or type 2 myocardial ischemia) myocardial injury. Considering that 44.8% of young patients with ischemic stroke in this cohort had no prior risk factors and that cardiac troponin was elevated in 80% of them, high troponin levels are likely the consequence of acute myocardial injury, which could play a role in the pathophysiology of acute ischemic stroke in young patients with COVID-19.
This is further supported by the higher proportion of elevated cardiac troponin found in young patients with COVID-19 with ischemic stroke (80%) compared to historical cohorts of patients with ischemic stroke (40%)44 and to other age groups in this cohort. Furthermore, a recent study showed that although only 5% of recovered patients had significantly elevated troponin levels at a median of 71 days after COVID-19 diagnosis, 78% had ongoing cardiac involvement and 60% had signs of myocardial inflammation on cardiac MRI.45 This suggests that myocarditis is a potential stroke mechanism in COVID-19.45
We identified specific stroke phenotypes consistently associated with increased mortality. Among patients with any stroke, cluster 3 was associated with >3 times higher in-hospital mortality than each of the remaining 2 clusters or both of them considered together.
This stroke phenotype was characterized by the interplay of older age, a higher burden of risk factors and comorbid conditions, and a higher proportion of severe or critical COVID-19 cases. Among these variables, the only one significantly associated with in-hospital mortality on unadjusted univariable analyses was severe COVID-19 respiratory symptoms (OR 6.56, 95% CI 2.91–14.76, p < 0.001). Thus, COVID-19 severity likely plays a major role in the risk of death of patients with stroke. Similar results were found among patients with ischemic stroke.
This work represents a comprehensive review of available evidence addressing the relationship between COVID-19 and stroke based on a large number of cases identified through a systematic search and pooled with previously unpublished cases. Our results should be interpreted in the context of the study limitations.
First, although the study sample is relatively large, its size still precludes multivariable regression analyses for ischemic strokes. Second, because most of the source data were pooled from case series and reports, completeness was not ideal. As a consequence, we were not able to inform about stroke severity (only a few studies reported NIH Stroke Scale scores), stroke mechanisms, regional differences, social determinants of health, or race.
Third, we found moderate publication bias (funnel plots and risk of bias in nonrandomized studies of interventions tool). Due to the relatively low number of studies included in the meta-analyses, funnel plots could have underestimated the risk of bias. Fourth, data used in this study are likely subject to the consequences of publication bias (e.g., reporting more severe cases or cases of LVO in young patients).
Fifth, these results may not be generalizable to other populations such as nonhospitalized patients. To mitigate these limitations and the previous knowledge bias about stroke in patients without COVID-19, we implemented an unsupervised learning approach by applying cluster analyses, which allowed us to establish clinical phenotypes associated with increased risk of death.
This was possible by comprehensive documentation of other important variables. Rather than focusing on single variables and their individual association with outcomes, these analyses allowed the characterization of the interplay of clinical characteristics, risk factors, demographics, and comorbid conditions as a whole and their association with in-hospital mortality.
We found that the frequency of stroke occurrence is high among hospitalized patients with COVID-19. In-hospital mortality is also exceedingly higher than previously reported in patients without COVID-19 with stroke. LVO is twice as frequent as previously reported, and its prevalence is high across all age groups, even in the absence of risk factors or comorbid conditions, suggesting the role of COVID-19–related hypercoagulability.
Specific clinical phenotypes characterized by the interplay of older age, a higher burden of cardiovascular comorbid conditions, and severe COVID-19 respiratory symptoms were associated with a substantial increase in the risk of death. COVID-19 severity seems to be the major determinant of death. Our findings should serve as information for guiding prognostication, resource allocation, and counseling of patients and their families.
reference link :https://n.neurology.org/content/95/24/e3373
Journal information:Neurology
