key: cord-326626-ixxk6plf
authors: Akhtar, Naveed; Abid, Fatma Ben; Kamran, Saadat; Singh, Rajvir; Imam, Yahia; AlJerdi, Salman; AlMaslamani, Muna; Shuaib, Ashfaq
title: Characteristics and Comparison of 32 COVID-19 and Non-COVID-19 Ischemic Strokes and historical stroke patients.
date: 2020-11-02
journal: J Stroke Cerebrovasc Dis
DOI: 10.1016/j.jstrokecerebrovasdis.2020.105435
sha: 
doc_id: 326626
cord_uid: ixxk6plf

INTRODUCTION: : The presence of COVID-19 infection may increase the risk of thrombotic events including ischemic strokes. Whilst a number of recent reports suggest that COVID-19 associated stroke tends to be severe, there is limited data on the effects of COVID-19 in prospective registries. PATIENT AND METHODS: : To determine how COVID-19 infection may affect cerebrovascular disease, we evaluated the ischemic stroke sub-types, clinical course and outcomes prior to and during the pandemic in Qatar. The Hamad General Hospital (HGH) stroke database was interrogated for stroke admissions during the last 4 months of 2019 and January-May 2020. RESULTS: : In Qatar the number of confirmed cases of COVID-19 increased from only 2 in February to 779 in March, 12,628 in April and 45,501 in May. Stroke admissions to HGH declined marginally from an average of 97/month for six pre-COVID months to 72/month in March – May. There were 32 strokes that were positive for COVID-19. When compared to non-COVID-19 stroke during the three months of the pandemic, COVID-19 patients were younger with significantly lower rates of hypertension, diabetes and dyslipidemia. COVID-19 positive patients had more cortical strokes (34.4% vs 5.6%; p= 0.001), severe disease (NIHSS >10: 34.4% vs 16.7%; p=0.001) prolonged hospitalization and fewer with good recovery (mRS 0-2: 28.1% vs 51.9%; p= 0.001). CONCLUSIONS: : When compared to six pre-COVID-19 months, the number of ischemic stroke admissions during the three months of the pandemic declined marginally. COVID-19 positive patients were more likely to have a large cortical stroke with severe symptoms and poor outcome.

The number of confirmed cases of COVID-19 worldwide has exceeded 31,000,000 with more than 901,000 confirmed deaths as of September 21, 2020 (1). The virus mainly manifests through respiratory involvement with fever, cough, shortness of breath and other pulmonary symptoms (2) . Neurological symptoms, including headaches, dizziness, myalgias, alteration in levels of consciousness and altered mental status are common symptoms and may occur in more than 50% of hospitalized patients (3) . In one recent study, acute stroke has been reported in 2.5% of consecutive COVID-19 related hospital admissions (4) . Whereas neuropathological examination reveals diffuse hypoxic injury in severe cases, likely related to the severe hypoxemia, there was no evidence for thrombosis, overt vasculitis or encephalitis in a series of 18 autopsy cases (5) .

Despite the lack of overt intracranial thrombosis in the autopsy study (4) there is however evidence that COVID-19 infection has profound effects on the cardiovascular system including an increased risk of venous thrombosis and pulmonary embolism (6) , myocardial injury (7) and stroke (8, 9, 10; 11) . In addition, an interesting report from New York suggests that during the COVID-19 pandemic, there was a higher likelihood for imaging-confirmed acute ischemic stroke to harbor the virus during 'code-stroke' activation (12) .

Another interesting observation from several centers across the globe have shown that transient ischemic stroke (TIA) and stroke admissions have decreased significantly during the COVID-19 pandemic (9, 13, 14, 15) . There was a decrease in the number of strokes in Piacenza (a city of 280,000 inhabitants), an important epicenter of the disease in Northern Italy (13) . The monthly admissions decreased from an average of 51 cases to only 6 over a 5-week period (13) . Large studies from China (8) , Brazil (13, 14) , and Spain (9) reported an approximately 25% decrease in ED admissions during the peak weeks of the pandemic. Additional reports suggest an increase in COVID-19-related severe stroke, especially in younger patients (10) . This may be related to a possible pro-coagulant state seen with COVID-19 infection (16) . A decrease in hospital admissions of cardiovascular disease and acute coronary syndromes has also been observed in EDs during the recent COVID-19 pandemic (17) . The numbers of cardiac catheterization laboratory STEMI activations decreased by 38% in the USA (18) and 40 % in Spain (19) as the pandemic spread in these countries. Although a decrease in minor ailments and trauma-related visits may be related to a fear of exposure to the virus during visits to the ED, the actual reason for significant decreases in ED visits for more serious illnesses remain unclear.

These reports unfortunately provide insufficient details on the relationship of COVID-19 infection and stroke. Prospective hospital-based or community registries are important to study the effects of pandemics on the types of vascular diseases (20) . Registries may also provide important insight about time-sensitive healthcare delivery metrics such as door-to-intervention times, as was recently documented from treatment delays of myocardial infarctions in Hong Kong (15) . Similarly, time-sensitive management of emergencies including thrombolysis in acute stroke may also be affected by the COVID-19 pandemic.

The main objective of the present study is to compare the types of ischemic strokes in patients with or without confirmed COVID-19 infection to a busy tertiary care hospital during the pandemic. We also determined if there were any differences in the rates of complications during hospitalization and short-term prognosis between acute stroke patients with COVID-19 infections and patients with acute stroke and no COVID-19 infection.

The Qatar Stroke Database prospectively collects information on all acute stroke patients For the present study, we evaluated the monthly rates of confirmed ischemic stroke admissions to the hospital for the last 4 months in 2019, prior to the onset of COVID-19 pandemic. We compared this to the first 5 months of 2020 as the pandemic was being documented in China and Europe (January-February) and as COVID-19 cases began to be diagnosed in Qatar (March-May).

We documented all patients with ischemic stroke who also were diagnosed with COVID-19. Any symptoms related to the viral infection (fever, cough, sore throat and severity of pulmonary illness) were documented. Particular attention was given to where the patient was admitted (ICU vs stroke ward), medical complications and treatment offered were all documented. Where available, we also documented changes in the laboratory markers of inflammation in COVID-19 subjects.

Descriptive statistics in the form of mean and standard deviations for continuous variables and frequency with percentages for categorical variables were performed. One-way ANOVAs were performed to see significant mean level differences for all continuous variables according to Pre-COVID-19 ischemic stroke, COVID-19 Negative ischemic stroke and COVID-19 positive categories. Student t tests were applied for continuous variables to see significant mean level differences between subcortical strokes or small vessel disease (SVD) vs cortical or large vessel disease (LVD), and "No evidence of pneumonia" on chest x-ray vs "Bilateral pneumonia" on chest X-ray. Chi-square tests were applied to see association of categorical variables according to Pre-COVID-19 ischemic stroke, COVID-19 negative ischemic stroke and COVID-19 positive cases, subcortical strokes or SVD vs cortical or LVD; and "No evidence of pneumonia" on chest

x-ray vs "bilateral pneumonia" on chest X-ray respectively. Multivariate logistic regression analysis was used for the significant and important variables at univariate analysis to association of risk factors to COVID-19 positive group. Adjusted Odds Ratios with 95% C.I. and P values were presented in the tables. ROC curve with C-statistics was used to see discriminate power of the model for the COVID-19 positive cases. P value 0.05 (two tailed) was considered statistically significant level. The statistical tests were performed in IBM SPSS Statistics ver. 26 (IBM, Armonk, USA).

During the 9 months of the study, there were 833 patients [age; 54.3 ± 13.5 male/female 675 (81%)/158 (19%)] admitted to HGH with a diagnosis of acute ischemic stroke. The higher percentage of males reflects the demographics of Qatar with a predominantly male expatriate population as has been previously reported (21, 22) . There were 585 admissions in the 6 months prior to when COVID-19 cases were confirmed in Qatar (average monthly admissions to HGH (Table 3) . C-statistics was 0.78 with 95% C.I.: 0.69 -0.87, suggesting the model's good ability to discriminate for COVID cases (Figure 2 ).

To our knowledge, this is the first study that compares COVID-19 patients to non-COVID-19 patients within a prospectively collected stroke database. Similar to previous case reports and case-controlled studies, from USA (10), Iran (26), Dubai (27) , France (28) and China (8), a third of our COVID-19 positive patients had severe disease, required ICU admissions, stayed longer in hospital and had fewer subjects with good outcome. These patients likely represent a subset of stroke patients in whom the viral infection likely contributed to a prothrombotic state resulting in vascular occlusions and large strokes. In the remainder of patients, especially those presenting with small vessel disease, the viral infection was perhaps coincidental and did not influence the clinical course and outcome of the illness. We did not observe any delays in times from onset to hospital admission, or any differences in the rates of thrombolysis or thrombectomies in patients with or without COVID-19 infection. The higher rates of admission to ICU in COVID-19 positive patients is likely related to the severity of illness at presentation.

In patients with COVID-19 infection, there is increasing evidence for activation of inflammatory and thrombosis pathways. Case series suggest a high incidence of venous thrombosis despite anticoagulation treatment (6), myocarditis (7) and stroke (8) (9) (10) . Similar to our patients, COVID-19 positive patients from other reports with acute stroke were younger, have fewer vascular risk factors and many had recurrent thrombi in the large cranial arteries (8-10). The longer hospitalization in our COVID-19 positive patients was also likely related to more severe disease as evidenced by higher NIHSS scores and more cortical involvement. Such patients were also less likely to have a favorable outcome on discharge despite longer length of hospitalization. In a recent study from Europe, patients with COVID-19 associated ischemic strokes were more severe with worse functional outcome and higher mortality than non-COVID-19 ischemic strokes (29) .

An intriguing observation during the COVID-19 pandemic is the decreasing number of stroke admissions reported from a number of countries (9, (13) (14) (15) . The reason for the decrease in rates of cardiovascular disease remains unclear. Perhaps the most important reason may be the fear of exposure to COVID-19 in hospitals and thus opting for staying home to minimize the risk. This may explain the decrease in the number of "stroke mimics" admission to hospital in our study and fewer hospitalization of patients with TIAs and milder strokes in the study from Brazil (14) . There are strengths to our study. The Qatar Stroke Database is very robust and has prospectively recorded stroke trends in the country for more than 7 years. We did not document major changes in the admission of ischemic stroke sub-types during the months preceding and during the three months of the COVID-19 pandemic. Whereas other studies comprised of case reports or case series, we compare profiles of non-COVID-19 acute stroke patients before and during the pandemic with acute stroke patients who were COVID-19 positive. Our study reveals that COVID-19 positive patients were more likely to be sicker, had more cortical involvement and had prolonged hospitalization. In addition, fewer patients had a good recovery at discharge as measured with mRS.

The study has some limitations. The study period was only three months and may not be sufficient to determine if these were related to COVID-19 infections. We did not document the relationship of the illness to the severity of COVID-19-related laboratory abnormalities. We also do not have enough follow-up data on the patients seen during the pandemic to adequately document the changes in outcomes.

The onset of COVID-19 pandemic has been associated with a decrease in non-COVID-19 associated admissions to hospitals in Asia, Europe and North America. We present data from a prospective stroke database showing that ischemic stroke decreased marginally during the COVID-19 pandemic. We also review the presenting features and clinical course of 32 COVID-19 positive patients. Our data suggests that in a third of acute stroke patients, the viral infection results in a more severe disease, whereas in the remainder, the COVID-19 illness has very little effect on the course of the illness. In summary, we believe that the spectrum of acute stroke in the COVID-19 includes three presentations; stroke and no COVID-19 infection, stroke with incidental COVID-19 infection and COVID-19 induced prothrombotic ischemic stroke. 

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