Stroke During the Convalescent Phase of Asymptomatic COVID-2019 in Men | Cerebrovascular Disease | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Acute Ischemic Stroke During the Convalescent Phase of Asymptomatic COVID-2019 Infection in Men

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  Is the risk of acute ischemic stroke (AIS) elevated in patients in the convalescent phase of an asymptomatic COVID-19 infection?

Findings  In this case series of 18 male adults aged 50 years or younger who presented with AIS during the convalescent phase of an asymptomatic COVID-19 infection confirmed by a positive SARS-CoV-2 serological (antibodies) test result, the median onset of stroke was 2 months after the diagnosis of COVID-19.

Meaning  Results of this study suggest a persistent increased risk of AIS in individuals with asymptomatic COVID-19 months after serological diagnosis, warranting stroke units to be on alert and use SARS-CoV-2 serological testing.

Abstract

Importance  Acute ischemic stroke (AIS) is a known neurological complication in patients with respiratory symptoms of COVID-19 infection. However, AIS has not been described as a late sequelae in patients without respiratory symptoms of COVID-19.

Objective  To assess AIS experienced by adults 50 years or younger in the convalescent phase of asymptomatic COVID-19 infection.

Design, Setting, and Participants  This case series prospectively identified consecutive male patients who received care for AIS from public health hospitals in Singapore between May 21, 2020, and October 14, 2020. All of these patients had laboratory-confirmed asymptomatic COVID-19 infection based on a positive SARS-CoV-2 serological (antibodies) test result. These patients were individuals from South Asian countries (India and Bangladesh) who were working in Singapore and living in dormitories. The total number of COVID-19 cases (54 485) in the worker dormitory population was the population at risk. Patients with ongoing respiratory symptoms or positive SARS-CoV-2 serological test results confirmed through reverse transcriptase–polymerase chain reaction nasopharyngeal swabs were excluded.

Main Outcomes and Measures  Clinical course, imaging, and laboratory findings were retrieved from the electronic medical records of each participating hospital. The incidence rate of AIS in the case series was compared with that of a historical age-, sex-, and ethnicity-matched national cohort.

Results  A total of 18 male patients, with a median (range) age of 41 (35-50) years and South Asian ethnicity, were included. The median (range) time from a positive serological test result to AIS was 54.5 (0-130) days. The median (range) National Institutes of Health Stroke Scale score was 5 (1-25). Ten patients (56%) presented with a large vessel occlusion, of whom 6 patients underwent intravenous thrombolysis and/or endovascular therapy. Only 3 patients (17%) had a possible cardiac source of embolus. The estimated annual incidence rate of AIS was 82.6 cases per 100 000 people in this study compared with 38.2 cases per 100 000 people in the historical age-, sex-, and ethnicity-matched cohort (rate ratio, 2.16; 95% CI, 1.36-3.48; P < .001).

Conclusions and Relevance  This case series suggests that the risk for AIS is higher in adults 50 years or younger during the convalescent period of a COVID-19 infection without respiratory symptoms. Acute ischemic stroke could be part of the next wave of complications of COVID-19, and stroke units should be on alert and use serological testing, especially in younger patients or in the absence of traditional risk factors.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Accepted for Publication: March 4, 2021.

Published: April 22, 2021. doi:10.1001/jamanetworkopen.2021.7498

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Tu TM et al. JAMA Network Open.

Corresponding Author: Tian Ming Tu, MRCP, Department of Neurology, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433 (tu.tian.ming@singhealth.com.sg).

Author Contributions: Dr Tu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Tu, Seet, Umapathi.

Acquisition, analysis, or interpretation of data: Tu, Seet, Tham, Koh, Chiew, De Leon, Chua, Hui, S. S. Y. Tan, Vasoo, B. Y.-Q. Tan, Tambyah, Yeo.

Drafting of the manuscript: Tu, Seet, Koh, De Leon, Chua, B. Y.-Q. Tan, Tambyah.

Critical revision of the manuscript for important intellectual content: Tu, Tham, Chiew, Hui, S. S. Y. Tan, Vasoo, B. Y.-Q. Tan, Umapathi, Tambyah, Yeo.

Statistical analysis: Tu, De Leon, B. Y.-Q. Tan.

Administrative, technical, or material support: Tham, Koh, Chiew, Hui, S. S. Y. Tan, B. Y.-Q. Tan, Umapathi, Tambyah, Yeo.

Supervision: Umapathi, Yeo.

Conflict of Interest Disclosures: Dr Tambyah reported receiving grants paid to the institution from Roche, Shionogi, Arcturus, and Johnson and Johnson as well as honorarium paid to the institution from AJ Biologics. Dr Yeo reported receiving personal fees from Stryker and grants from the National Medical Research Council of Singapore outside the submitted work. No other disclosures were reported.

References
1.
Ji  T , Chen  HL , Xu  J ,  et al.  Lockdown contained the spread of 2019 novel coronavirus disease in Huangshi City, China: early epidemiological findings.   Clin Infect Dis. 2020;71(6):1454-1460. doi:10.1093/cid/ciaa390 PubMedGoogle ScholarCrossref
2.
Bi  Q , Wu  Y , Mei  S ,  et al.  Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study.   Lancet Infect Dis. 2020;20(8):911-919. doi:10.1016/S1473-3099(20)30287-5 PubMedGoogle ScholarCrossref
3.
Furuse  Y , Sando  E , Tsuchiya  N ,  et al.  Clusters of coronavirus disease in communities, Japan, January-April 2020.   Emerg Infect Dis. 2020;26(9):2176-2179. doi:10.3201/eid2609.202272 PubMedGoogle Scholar
4.
Dong  Y , Mo  X , Hu  Y ,  et al.  Epidemiology of COVID-19 among children in China.   Pediatrics. 2020;145(6):e20200702. doi:10.1542/peds.2020-0702 PubMedGoogle Scholar
5.
Shi  SM , Bakaev  I , Chen  H , Travison  TG , Berry  SD .  Risk factors, presentation, and course of coronavirus disease 2019 in a large, academic long-term care facility.   J Am Med Dir Assoc. 2020;21(10):1378-1383.e1. doi:10.1016/j.jamda.2020.08.027PubMedGoogle ScholarCrossref
6.
Rivett  L , Sridhar  S , Sparkes  D ,  et al; CITIID-NIHR COVID-19 BioResource Collaboration.  Screening of healthcare workers for SARS-CoV-2 highlights the role of asymptomatic carriage in COVID-19 transmission.   Elife. 2020;9:e58728. doi:10.7554/eLife.58728PubMedGoogle Scholar
7.
Rubin  R .  As their numbers grow, COVID-19 “long haulers” stump experts.   JAMA. 2020;324(14):1381-1383. doi:10.1001/jama.2020.17709PubMedGoogle ScholarCrossref
8.
Merkler  AE , Parikh  NS , Mir  S ,  et al.  Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza.   JAMA Neurol. 2020;77(11):1366-1372. doi:10.1001/jamaneurol.2020.2730 PubMedGoogle ScholarCrossref
9.
Tan  YK , Goh  C , Leow  AST ,  et al.  COVID-19 and ischemic stroke: a systematic review and meta-summary of the literature.   J Thromb Thrombolysis. 2020;50(3):587-595. doi:10.1007/s11239-020-02228-y PubMedGoogle ScholarCrossref
10.
Bikdeli  B , Madhavan  MV , Jimenez  D ,  et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function.  COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review.   J Am Coll Cardiol. 2020;75(23):2950-2973. doi:10.1016/j.jacc.2020.04.031 PubMedGoogle ScholarCrossref
11.
Zhang  Y , Xiao  M , Zhang  S ,  et al.  Coagulopathy and antiphospholipid antibodies in patients with COVID-19.   N Engl J Med. 2020;382(17):e38. doi:10.1056/NEJMc2007575 PubMedGoogle Scholar
12.
Goshua  G , Pine  AB , Meizlish  ML ,  et al.  Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study.   Lancet Haematol. 2020;7(8):e575-e582. doi:10.1016/S2352-3026(20)30216-7 PubMedGoogle ScholarCrossref
13.
Oxley  TJ , Mocco  J , Majidi  S ,  et al.  Large-vessel stroke as a presenting feature of COVID-19 in the young.   N Engl J Med. 2020;382(20):e60. doi:10.1056/NEJMc2009787 PubMedGoogle Scholar
14.
Ministry of Health, Singapore. COVID-19 interactive situation report. Updated October 14, 2020. Accessed October 14, 2020. https://www.moh.gov.sg/docs/librariesprovider5/local-situation-report/situation-report---14-oct-2020.pdf
15.
De Deyn  MLZQ , Ng  QX , Loke  W , Yeo  WS .  A tale of two cities: a comparison of Hong Kong and Singapore’s early strategies for the coronavirus disease 2019 (COVID-19).   J Infect. 2020;81(3):e51-e52. doi:10.1016/j.jinf.2020.06.058 PubMedGoogle ScholarCrossref
16.
Koh  JS , De Silva  DA , Quek  AML ,  et al.  Neurology of COVID-19 in Singapore.   J Neurol Sci. 2020;418:117118. doi:10.1016/j.jns.2020.117118 PubMedGoogle Scholar
17.
von Elm  E , Altman  DG , Egger  M , Pocock  SJ , Gøtzsche  PC , Vandenbroucke  JP ; STROBE Initiative.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.   Lancet. 2007;370(9596):1453-1457. doi:10.1016/S0140-6736(07)61602-X PubMedGoogle ScholarCrossref
18.
Ministry of Health, Singapore. Singapore Stroke Registry annual report 2018. Health Promotion Board; National Registry of Diseases Office. June 9, 2020. Accessed October 14, 2020. https://www.nrdo.gov.sg/docs/librariesprovider3/default-document-library/ssr-web-report-2018.pdf?sfvrsn=58eb7c4c_0
19.
Rothman  KJ .  Modern Epidemiology. Little Brown & Co; 1986.
20.
Adams  HP  Jr , Bendixen  BH , Kappelle  LJ ,  et al; TOAST Investigators.  Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial.   Stroke. 1993;24(1):35-41. doi:10.1161/01.STR.24.1.35 PubMedGoogle ScholarCrossref
21.
Department of Statistics Singapore. M810011—Singapore residents by age group, ethnic group and sex, end June, annual. Updated September 24, 2020. Accessed October 14, 2020. https://data.gov.sg/dataset/resident-population-by-ethnicity-gender-and-age-group
22.
Avula  A , Nalleballe  K , Narula  N ,  et al.  COVID-19 presenting as stroke.   Brain Behav Immun. 2020;87:115-119. doi:10.1016/j.bbi.2020.04.077 PubMedGoogle ScholarCrossref
23.
Rothstein  A , Oldridge  O , Schwennesen  H , Do  D , Cucchiara  BL .  Acute cerebrovascular events in hospitalized COVID-19 patients.   Stroke. 2020;51(9):e219-e222. doi:10.1161/STROKEAHA.120.030995 PubMedGoogle ScholarCrossref
24.
Sethuraman  N , Jeremiah  SS , Ryo  A .  Interpreting diagnostic tests for SARS-CoV-2.   JAMA. 2020;323(22):2249-2251. doi:10.1001/jama.2020.8259 PubMedGoogle ScholarCrossref
25.
Ferroli  P , Villa  C , Ciuffi  A , Gubertini  G , Broggi  M .  Long lasting hypercoagulability after subclinical COVID-19.   J Thromb Thrombolysis. 2020;50(4):822-824. doi:10.1007/s11239-020-02215-3 PubMedGoogle ScholarCrossref
26.
Tsang  ACO , You  J , Li  LF ,  et al.  Burden of large vessel occlusion stroke and the service gap of thrombectomy: a population-based study using a territory-wide public hospital system registry.   Int J Stroke. 2020;15(1):69-74. doi:10.1177/1747493019830585 PubMedGoogle ScholarCrossref
27.
Kim  BJ , Kim  JS .  Ischemic stroke subtype classification: an Asian viewpoint.   J Stroke. 2014;16(1):8-17. doi:10.5853/jos.2014.16.1.8 PubMedGoogle ScholarCrossref
28.
Klok  FA , Kruip  MJHA , van der Meer  NJM ,  et al.  Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: an updated analysis.   Thromb Res. 2020;191:148-150. doi:10.1016/j.thromres.2020.04.041 PubMedGoogle ScholarCrossref
29.
Beyrouti  R , Adams  ME , Benjamin  L ,  et al.  Characteristics of ischaemic stroke associated with COVID-19.   J Neurol Neurosurg Psychiatry. 2020;91(8):889-891. doi:10.1136/jnnp-2020-323586 PubMedGoogle ScholarCrossref
30.
Fournier  M , Faille  D , Dossier  A ,  et al.  Arterial thrombotic events in adult inpatients with COVID-19.   Mayo Clin Proc. 2021;96(2):295-303. doi:10.1016/j.mayocp.2020.11.018 PubMedGoogle ScholarCrossref
31.
von Meijenfeldt  FA , Havervall  S , Adelmeijer  J ,  et al.  Sustained prothrombotic changes in COVID-19 patients 4 months after hospital discharge.   Blood Adv. 2021;5(3):756-759. doi:10.1182/bloodadvances.2020003968 PubMedGoogle ScholarCrossref
32.
Tan  SS , Saw  S , Chew  KL ,  et al.  Comparative clinical evaluation of the Roche Elecsys and Abbott SARS-CoV-2 serology assays for COVID-19.   Arch Pathol Lab Med. 2020. doi:10.5858/arpa.2020-0499-SAPubMedGoogle Scholar
33.
The Lancet Haematology.  COVID-19 and thrombosis: a continuing story.   Lancet Haematol. 2021;8(2):e95. doi:10.1016/S2352-3026(21)00002-8 PubMedGoogle Scholar
34.
Rosadas  C , Randell  P , Khan  M , McClure  MO , Tedder  RS .  Testing for responses to the wrong SARS-CoV-2 antigen?   Lancet. 2020;396(10252):e23. doi:10.1016/S0140-6736(20)31830-4 PubMedGoogle Scholar
35.
Yamaoka  Y , Jeremiah  SS , Miyakawa  K ,  et al.  Whole nucleocapsid protein of SARS-CoV-2 may cause false positive results in serological assays.   Clin Infect Dis. 2020;ciaa637. doi:10.1093/cid/ciaa637 PubMedGoogle Scholar
36.
Ladikou  EE , Sivaloganathan  H , Milne  KM ,  et al.  Von Willebrand factor (vWF): marker of endothelial damage and thrombotic risk in COVID-19?   Clin Med (Lond). 2020;20(5):e178-e182. doi:10.7861/clinmed.2020-0346 PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close