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• Corona viruses and Stroke
  Thirugnanam Umapathi
  Published on: 1 May 2020

• Published on: 1 May 2020

  Corona viruses and Stroke

  • Thirugnanam Umapathi, Senior Consultant Neurologist National Neuroscience Institute, Singapore

  Dear Editor,

  The editorial by Manji et al.1 on the neurology of the COVID-19 pandemic cites Mao et al2.’s report describing 5 ischemic strokes in 214 COVID-19 patients. Helms et al3,. and Zhang et al4. have also since reported ischemic stroke in patients with severe SARS-CoV-2 infection, with the latter linking stroke to antiphospholipid antibodies4. In addition, Oxley et al. describe large-vessel stroke in 5 young patients5. In this context, I would like to highlight our 2003 study of ischemic stroke in severe SARS-CoV-1 infection, the corona virus responsible for Severe Acute Respiratory Syndrome (SARS)6. Five out of a total of 206 SARS patients in the country developed large artery ischemic stroke7, four of whom were critically ill. They were not significantly older (56±13 years) than other critically-ill SARS patients (50±16 years, Anova p=0.45). Besides episodes of hypotension, we suspected thromboembolism as a possible mechanism of stroke. Four of the eight SARS patients, who had autopsy examination, revealed evidence of pulmonary thromboemboli8. One was a 39-year-old man, with no stroke risk factors, who died two weeks after contracting SARS; his autopsy revealed unilateral occipital lobe infarction, sterile vegetations on multiple valves, deep venous thrombosis and pulmonary embolism. This prompted the subsequent use of low molecular weight heparin (LMWH) in critically-ill patients, at doses to achieve anti-Xa levels of 0.5-1.0IU/ml. Nevertheless, one-thir...

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  Dear Editor,

  The editorial by Manji et al.1 on the neurology of the COVID-19 pandemic cites Mao et al2.’s report describing 5 ischemic strokes in 214 COVID-19 patients. Helms et al3,. and Zhang et al4. have also since reported ischemic stroke in patients with severe SARS-CoV-2 infection, with the latter linking stroke to antiphospholipid antibodies4. In addition, Oxley et al. describe large-vessel stroke in 5 young patients5. In this context, I would like to highlight our 2003 study of ischemic stroke in severe SARS-CoV-1 infection, the corona virus responsible for Severe Acute Respiratory Syndrome (SARS)6. Five out of a total of 206 SARS patients in the country developed large artery ischemic stroke7, four of whom were critically ill. They were not significantly older (56±13 years) than other critically-ill SARS patients (50±16 years, Anova p=0.45). Besides episodes of hypotension, we suspected thromboembolism as a possible mechanism of stroke. Four of the eight SARS patients, who had autopsy examination, revealed evidence of pulmonary thromboemboli8. One was a 39-year-old man, with no stroke risk factors, who died two weeks after contracting SARS; his autopsy revealed unilateral occipital lobe infarction, sterile vegetations on multiple valves, deep venous thrombosis and pulmonary embolism. This prompted the subsequent use of low molecular weight heparin (LMWH) in critically-ill patients, at doses to achieve anti-Xa levels of 0.5-1.0IU/ml. Nevertheless, one-third of severe SARS patients developed venous thromboembolism including pulmonary embolism6,7. Three of the 5 stroke patients had also received LMWH. Three patients had unremarkable procoagulant work-up. While we did not measure D-dimer systematically 2 had evidence of disseminated intravascular coagulation, both whom died. Mao et al. and Oxley et al. highlight the possible significance of raised D-dimer in COVID-19 patients who developed stroke2,5. Furthermore, intravenous immunoglobulin (IVIg) was given empirically to 3 of our patients, at 2, 5 and 16 days before stroke onset, that could have compounded the thromboembolic risk.

  Experimental, albeit conflicting, evidence suggests that the SARS-CoV1 virus, which causes SARS, could activate transcription of a prothrombinase gene, coding Fibrinogen-like 2 (FGL2)9. FGL2 is a multi-functional protein that activates prothrombin to generate thrombin that in turn converts fibrinogen into fibrin, possibly explaining the extensive fibrin deposition in the lungs of SARS patients as well as inducing a prothrombotic state. Interestingly, the proteolytic activity of FGL2 is independent of factor X and cannot be inhibited by antithrombin III9, perhaps explaining LMWH’s apparent lack of efficacy in our patients.

  Ischemic stroke appears to be an infrequent complication of corona virus infections, occurring mainly in the very ill patients with multiple contributory co-morbidities. However, in contrast to SARS, which affected fewer than 9000 people globally COVID-19 has already infected more than 2 million, a sizeable proportion of whom are critically ill. Our experience with SARS prompts us to recommend vigilance against thromboembolism in general and specifically as a mechanism for ischemic stroke, particularly if empirical treatment with IVIg or convalescent plasma is attempted.

  References:
  1) Manji H, Carr AS, Brownlee WJ. Neurology in the time of covid-19. J Neurol Neurosurg Psychiatry. 2020 Apr 20. pii: jnnp-2020-323414.
  2) Ling Mao1; Huijuan Jin; Mengdie Wang1; et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. Published online.
  3) Helms J, Kremer S, Merdji H. Neurologic Features in Severe SARS-CoV-2 Infection.N Engl J Med. 2020 Apr 15. doi: 10.1056/NEJMc2008597.
  4) Zhang Y, Xiao M, Zhang S. Coagulopathy and Antiphospholipid Antibodies in Patients with Covid-19.N Engl J Med. 2020 Apr 8.
  5) 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 Apr 28.
  6) Umapathi T, Kor AC, Venketasubramanian N,et al. Large artery ischaemic stroke in severe acute respiratory syndrome (SARS). J Neurol. 2004;251(10):1227-31.
  7) Lew TW, Kwek TK, Tai D, et al. Acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome. JAMA 2003; 290(3):374-80.
  8) Chong PY, Chui P, Ling AE, Franks TJ,et al. Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis. Arch Pathol Lab Med 128:195–204
  9) Yang G, Hooper WC. Physiological functions and clinical implications of fibrinogen-like 2: A review World J Clin Infect Dis. 2013 Aug 25;3(3):37-46.

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  Conflict of Interest:
  None declared.

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