SARS-CoV-2 and Stroke Characteristics

A Report From the Multinational COVID-19 Stroke Study Group

Shima Shahjouei, MD, MPH; Georgios Tsivgoulis, MD, PhD, MSc; Ghasem Farahmand, MD; Eric Koza, MD Candidate; Ashkan Mowla, MD; Alireza Vafaei Sadr, PhD; Arash Kia, MD; Alaleh Vaghefi Far, MD; Stefania Mondello, MD, PhD, MPH; Achille Cernigliaro, PhD, MPH; Annemarei Ranta, MD, PhD; Martin Punter, PhD, MBChB; Faezeh Khodadadi, PharmD; Soheil Naderi, MD; Mirna Sabra, PhD; Mahtab Ramezani, MD; Ali Amini Harandi, MD; Oluwaseyi Olulana, MS; Durgesh Chaudhary, MBBS; Aicha Lyoubi, MD; Bruce C.V. Campbell, MD; Juan F. Arenillas, MD; Daniel Bock, MD; Joan Montaner, MD; Saeideh Aghayari Sheikh Neshin, MD; Diana Aguiar de Sousa, MD, PhD; Matthew S. Tenser, MD; Ana Aires, MD; Mercedes de Lera Alfonso, MD; Orkhan Alizada, MD; Elsa Azevedo, MD, PhD; Nitin Goyal, MD; Zabihollah Babaeepour, MD; Gelareh Banihashemi, MD; Leo H. Bonati, MD; Carlo W. Cereda, MD; Jason J. Chang, MD; Miljenko Crnjakovic, MD; Gian Marco De Marchis, MD; Massimo Del Sette, MD; Seyed Amir Ebrahimzadeh, MD, MPH; Mehdi Farhoudi, MD; Ilaria Gandoglia, MD; Bruno Gonçalves, MD; Christoph J. Griessenauer, MD; Mehmet Murat Hancı, MD; Aristeidis H. Katsanos, MD; Christos Krogias, MD; Ronen R. Leker, MD; Lev Lotman, MD; Jeffrey Mai, MD; Shailesh Male, MD; Konark Malhotra, MD; Branko Malojcic, MD, PhD; Teresa Mesquita, MD; Asadollah Mir Ghasemi, MD; Hany Mohamed Aref, MD; Zeinab Mohseni Afshar, MD; Jusun Moon, MD; Mika Niemelä, MD, PhD; Behnam Rezai Jahromi, MD; Lawrence Nolan, DO; Abhi Pandhi, MD; Jong-Ho Park, MD; João Pedro Marto, MD; Francisco Purroy, MD, PhD; Sakineh Ranji-Burachaloo, MD; Nuno Reis Carreira, MD; Manuel Requena, MD; Marta Rubiera, MD; Seyed Aidin Sajedi, MD; João Sargento-Freitas, MD; Vijay K. Sharma, MD; Thorsten Steiner, MD; Kristi Tempro, MD; Guillaume Turc, MD, PhD; Yasaman Ahmadzadeh, MD; Mostafa Almasi-Dooghaee, MD; Farhad Assarzadegan, MD; Arefeh Babazadeh, MD, MPH; Humain Baharvahdat, MD; Fabricio Buchadid Cardoso, MD, MPH; Apoorva Dev, PhD; Mohammad Ghorbani, MD; Ava Hamidi, MD; Zeynab Sadat Hasheminejad, MD; Sahar Hojjat-Anasri Komachali, MD; Fariborz Khorvash, MD; Firas Kobeissy, PhD; Hamidreza Mirkarimi, MD; Elahe Mohammadi-Vosough, MD; Debdipto Misra, MS; Ali Reza Noorian, MD; Peyman Nowrouzi-Sohrabi, PhD; Sepideh Paybast, MD; Leila Poorsaadat, MD; Mehrdad Roozbeh, MD; Behnam Sabayan, MD, PhD; Saeideh Salehizadeh, MD; Alia Saberi, MD; Mercedeh Sepehrnia, MD; Fahimeh Vahabizad, MD; Thomas Alexandre Yasuda, MD; Mojdeh Ghabaee, MD; Nasrin Rahimian, MD, MPH; Mohammad Hossein Harirchian, MD; Afshin Borhani-Haghighi, MD; Mahmoud Reza Azarpazhooh, MD; Rohan Arora, MD; Saeed Ansari, MD; Venkatesh Avula, MS; Jiang Li, MD, MPH; Vida Abedi, PhD; Ramin Zand, MD, MPH

Disclosures

Stroke. 2021;52(5):e117-e130. 

In This Article

Discussion

To our knowledge, this is to date the largest study that comprehensively presents the characteristics and stroke subtypes of stroke in SARS-CoV-2–infected patients at a multinational level. The results of our work indicated a relatively high number of young AIS patients, male predominance, asymptomatic SARS-CoV-2 infection in more than one-third of the AIS patients, a higher proportion of LVO strokes, and a low rate of small artery occlusion and lacunar infarcts. We also noted significant differences regarding the TOAST criteria in both regional and health expenditure subgroups, as well as higher NIHSS among countries with lower health expenditure.

Regarding the characteristics of patients with AIS, 44.5% (126 of 283 patients) had LVOs, without any age or sex predominance. This rate is comparable to a similar report from New York on stroke patients with SARS-CoV-2 infection.[31] In general, LVOs accounted for 24% to 46% of AIS worldwide.[32] If the definition of the LVOs is limited to internal carotid artery, middle cerebral artery (M1 and M2), anterior cerebral artery (A1), posterior cerebral artery (P1), intracranial vertebral artery, and basilar artery, similar to our study, the risk of LVO drops to 24% to 38%.[33,34] Considering this definition, we observed a considerably higher rate of LVOs among our patients. In our study, 13.6% of AIS patients received IVT and 7.4% underwent mechanical thrombectomy. These rates are similar to the multinational study on 174 AIS SARS-CoV-2–infected patients (12.7% IVT, 6.9% IVT and thrombectomy, and 5.2% mechanical thrombectomy).[35]

Based on the TOAST classification, large artery atherosclerosis accounts for 33% of strokes in our study, which is higher than reports from worldwide population-based studies (19%–23%).[36,37] SVO accounted for stroke etiology in 10% of our patients, and analysis of neuroimaging patterns showed 10.2% lacunar infarcts. These rates are lower than worldwide population-based studies—21% to 44% SVO[37,38] and 21% to 30% lacunar infarcts.[39,40] In Europe, SVO was present among 4.1% of patients in this study versus 12% to 31% of stroke patients in previous population studies.[41–47] Lacunar infarcts were detected in 9.3% of our AIS patients versus 14% to 31% of other population studies.[43,48–50] In the North and South America, these rates were 5.3% versus 15% to 18%[37,51] for SVO, and 9.1% versus 13% to 18% for lacunar infarcts.[37,40] Similarly, in the Middle Eastern countries, we observed 18.3% SVO versus 20% to 25% in previous reports[52–55] and 11.3% lacunar infarcts versus 19% to 26% in the previous population studies.[55–57]

Higher rates of LVO and large artery atherosclerosis strokes and lower rates of SVO and lacunar infarcts among patients in our study may present a predilection of the virus for inducing a certain type of stroke. Similar to our findings, other reports on SARS-CoV-2–infected stroke patients suggested a lower rate of SVO and lacunar infarct and a higher risk of LVO strokes among infected patients with SARS-CoV-2.[58–60] However, lacunar infarctions and SVO are more likely to produce milder deficits.[39,61–63] During the COVID-19 pandemic, patients with mild-to-moderate stroke symptoms were less likely to present at medical centers.[4,59] In addition, less severe stroke symptoms, mostly in critically ill patients or overwhelmed health centers, were more likely to be underdiagnosed. Our observation of a higher median NIHSS in countries with lower health expenditure and those in Middle Eastern countries may reflect a lower capacity of these centers for the diagnosis of mild stroke patients in the pandemic. It may also indicate that patients with mild stroke symptoms refused to present to the hospitals. In addition, we realized similar rates of LVOs and IVT in various geographic regions but a considerably lower rate of thrombectomy in countries with lower health expenditures. This observation may highlight a care disparity among countries. Future studies such as CASCADE[64] (Call to Action: SARS-CoV-2 and Cerebrovascular Disorders) are required to shed light on changes in stroke care protocols and hospitalization rate during the pandemic and compare it to the available infrastructure in each region.

Of notice, our study results showed a considerable number of young strokes. Although the definition of young stroke is debatable, the majority of the studies considered 50 or 55 years as the cutoff.[65] We realized that 36% of the AIS patients in our study were <55 years of age and 46% were <65 years of age (Tables V and VI in the Data Supplement). These proportions are considerably higher than the population-based reports before the pandemic (12.9%–20.7%).[66,67] The median age of AIS patients in our study was 68 (58–78) years. A case series from New York on 32 AIS patients with SARS-CoV-2 showed a median of 63 years for these patients. This finding was significantly lower than AIS patients without SARS-CoV-2 in the same study and same interval (median, 70 years) or the historical cohort of AIS patients presented to the same center in 2019 (median, 68.5 years).[31] A multinational study on 174 AIS patients with SARS-CoV-2 infection reported a median age of 71 years.[35]

Regarding cerebral venous sinus thrombosis and ICH, we had 18 stroke patients with CVST; the average age of patients was 49 years, 78% were <55 years of age, and >60% were women. Classically CVST is considered to occur in young adults, with the predilection of women.[68] However, the sex ratio varies widely—44.7% to 83.4% in women.[69] A systematic review on the sex ratio of 23 638 patients with CVST demonstrated an increasing trend among women (54.8% before 1981 to 69.8% after 2001), likely due to increased use of oral contraceptives.[70] Even though CVST patients in our study were younger than patients with other stroke subtypes, they were older than previously reported CVST patients without SARS-CoV-2 infection.[69–74] In addition, only 27.8% of the patients in our study had multiple sinus or venous involvement, which is considerably lower than previous reports in non–SARS-CoV-2–infected patients.[69,73,75] One reason might be the severe condition of the patients with multiple CVSTs that prevent the proper diagnosis of these patients.

Our study reported 91 patients with ICH. Among the patients with SAH (23), no aneurysm was detected in 69.5% of patients, which is higher than the reported 15% (5%–34%) spontaneous SAH among patients without SARS-CoV-2 infection.[76] We observed that 27.9% of IPH patients had no vascular risk factors or comorbidities. These patients had higher ICH score and younger age in comparison with other patients with IPH.

This work has several limitations. Despite that we included centers from multiple countries and presented a comprehensive panel of patients' characteristics, some of the specific laboratory parameters related to rare stroke causes (eg, antiphospholipid antibodies) were not included in this study. The collaborators tried to identify SARS-CoV-2 patients who presented with stroke as the first and only symptom, but the difficulty in measuring all symptoms related to COVID-19 (such as fatigue, anosmia, and ageusia) should be taken into consideration. In addition, not all the stroke patients in this study had a final disposition outcome, which limited our conclusion about in-hospital mortality. Although attempts were made to minimize the selection bias by including patients from different ethnicities, ecological conditions, and health care systems, this study may suffer from selection bias and low power in some subgroups. The authors attempt to assess the quality of data by Risk of Bias in Exposure Studies tool;[13] however, heterogeneity may exist among data obtained from multiple settings and multiple countries. Further studies that include a control population are warranted.

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