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• Mechanisms of ischaemic stroke in COVID-19: more data are needed
  David J Werring, Arvind Chandratheva
  Published on: 20 July 2020
• Mechanism for ischaemic stroke in COVID-19 - full evaluation needed
  Narayanaswamy Venketasubramanian
  Published on: 20 July 2020

• Published on: 20 July 2020

  Mechanisms of ischaemic stroke in COVID-19: more data are needed

  • David J Werring, Consultant Neurologist UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, Queen Square, London
  • Other Contributors:
    • Arvind Chandratheva, Consultant Neurologist

  Dear Editor,

  We thank Dr Venketasubramanian for their interest in our paper and for their considered response. We agree that some of our patients had alternative causes for stroke in addition to the marked prothrombotic and inflammatory state related to COVID-19, and that this point is relevant to interpreting our findings.

  We also agree that it can be difficult to define one specific “cause” for an ischaemic stroke despite detailed investigation, since many patients have a complex combination of risk factors (e.g. diabetes, hypertension, dyslipidaemia), disease processes (e.g. atherosclerosis, cerebral small vessel disease, atrial fibrillation), and potential mechanisms (e.g. large artery thrombo-embolism, cardiac embolism, small vessel occlusion). Nevertheless, our key observation was that a 16-day period we saw 6 strikingly similar patients, all with large vessel occlusions, elevated D-dimer, ferritin and CRP, 8-24 days following proven COVID-19 illness (and in one patient during the asymptomatic phase (1), suggesting the emergence of a distinct pattern of cerebral ischaemia associated with a prothrombotic inflammatory state.

  As correctly identified, Patient 2 had atrial fibrillation and previous mitral valve repair (not a metallic valve), but stroke occurred despite above-therapeutic anticoagulation with INR 3.6; this is unusual, so we concluded that the clear thrombotic state may therefore have been contributory (D-dimer 7,750). Similarly, al...

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  Dear Editor,

  We thank Dr Venketasubramanian for their interest in our paper and for their considered response. We agree that some of our patients had alternative causes for stroke in addition to the marked prothrombotic and inflammatory state related to COVID-19, and that this point is relevant to interpreting our findings.

  We also agree that it can be difficult to define one specific “cause” for an ischaemic stroke despite detailed investigation, since many patients have a complex combination of risk factors (e.g. diabetes, hypertension, dyslipidaemia), disease processes (e.g. atherosclerosis, cerebral small vessel disease, atrial fibrillation), and potential mechanisms (e.g. large artery thrombo-embolism, cardiac embolism, small vessel occlusion). Nevertheless, our key observation was that a 16-day period we saw 6 strikingly similar patients, all with large vessel occlusions, elevated D-dimer, ferritin and CRP, 8-24 days following proven COVID-19 illness (and in one patient during the asymptomatic phase (1), suggesting the emergence of a distinct pattern of cerebral ischaemia associated with a prothrombotic inflammatory state.

  As correctly identified, Patient 2 had atrial fibrillation and previous mitral valve repair (not a metallic valve), but stroke occurred despite above-therapeutic anticoagulation with INR 3.6; this is unusual, so we concluded that the clear thrombotic state may therefore have been contributory (D-dimer 7,750). Similarly, although patient 3 had atrial fibrillation, the D- dimer 16,100 is well in excess of what has previously been described in AF-related ischaemic stroke and seemed likely to be relevant.

  We agree that a detailed investigation for other potential causes and mechanisms is important, even in the presence of evidence of a prothrombotic state associated with COVID-19. All six patients had prolonged ward cardiac monitoring and - apart from the known atrial fibrillation in patients 2 and 3 - none of them had relevant rhythm abnormalities. Moreover, all patients had complete vascular imaging from aortic arch to the intracranially vessels, and no contributory vascular stenosis was identified in any of the patients. These findings strongly support a prothrombotic state as being relevant to the large-vessel occlusions we observed. Furthermore, our observations are consistent with several other recent reports (2-5).

  We acknowledge the research and clinical value of the TOAST (trial of ORG 10172 in acute stroke treatment) classification, which would probably categorise patients 2 and 3 as undetermined. However, we suggest that the prothrombotic and inflammatory syndrome seen after or during COVID-19 might interact with conventional vascular risk factors, disease processes and mechanism to result in large-vessel occlusion. Thus, acute treatment should be tailored to all relevant factors identified wherever possible. Therapeutic anticoagulation might be indicated but the intracranial bleeding risk needs to be considered in the presence of recent cerebral infarction.

  Further data are urgently needed to confirm whether the pattern of stroke that we reported in association with COVID-19 is consistently seen in other populations. Case-control studies of COVID-19 associated stroke and non-COVID-19 associated ischaemic stroke could be informative in determining whether, and if so, how, COVID-19 modifies the clinical manifestations of acute cerebrovascular disease.

  1. Beyrouti R, Adams ME, Benjamin L, et al. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg Psychiatry 2020 doi: 10.1136/jnnp-2020-323586 [published Online First: 2020/05/02]
  2. 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 doi: 10.1056/NEJMc2009787 [published Online First: 2020/04/29]
  3. Avula A, Nalleballe K, Narula N, et al. COVID-19 presenting as stroke. Brain Behav Immun 2020 doi: 10.1016/j.bbi.2020.04.077 [published Online First: 2020/05/04]
  4. Viguier A, Delamarre L, Duplantier J, et al. Acute ischemic stroke complicating common carotid artery thrombosis during a severe COVID-19 infection. J Neuroradiol 2020 doi: 10.1016/j.neurad.2020.04.003 [published Online First: 2020/05/04]
  5. Moshayedi P, Ryan TE, Mejia LLP, et al. Triage of Acute Ischemic Stroke in Confirmed COVID-19: Large Vessel Occlusion Associated With Coronavirus Infection. Front Neurol 2020;11:353. doi: 10.3389/fneur.2020.00353 [published Online First: 2020/04/21]

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  Conflict of Interest:
  None declared.

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• Published on: 20 July 2020

  Mechanism for ischaemic stroke in COVID-19 - full evaluation needed

  • Narayanaswamy Venketasubramanian, Neurologist Raffles Hospital, Singapore

  Dear Editor

  It is with great interest that I read the excellent paper by Beyrouti R, et al, on the characteristics of ischaemic stroke among patients with COVID-19(1). There is great interest in the prothromotic state seen in this illness – in this series, high D-dimer and fibrinogen levels in 6/6, positive lupus anticoagulant in 4/5, moderate anti-cardiolipin titres in 1/6.

  But I note that there are still some traditional mechanisms in these patients that may have been the cause of the stroke that may not have been fully elucidated, or if they were, were not reported in the paper. I see that patients 2 and 3 had atrial fibrillation, on warfarin, with supra-therapeutic (3.6, artificial heart valve) and sub-therapeutic (1.03) INRs respectively. The results of echocardiography and cardiac rhythm monitoring were not reported for any patient. Thus cardioembolism is still possible as a cause of stroke. Patients 2 to 5 had hypertension and at least one other atherosclerotic vascular risk factor (eg diabetes mellitus, hypercholesterolaemia, smoking, stroke). All patients save 1 was above 60 years of age. Vascular imaging was only reported for 2 cases (5 - CTA and 6 - MRA). Atherothromboelbolism may have caused stroke in some of the patients.

  I refer to case series of stroke seen during the 2002-2204 SARS epidemic, also due to a corona virus (2); all had large artery ischaemic strokes, at least 2 of 4 assessed patients had a cardioembolic source, with anot...

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  Dear Editor

  It is with great interest that I read the excellent paper by Beyrouti R, et al, on the characteristics of ischaemic stroke among patients with COVID-19(1). There is great interest in the prothromotic state seen in this illness – in this series, high D-dimer and fibrinogen levels in 6/6, positive lupus anticoagulant in 4/5, moderate anti-cardiolipin titres in 1/6.

  But I note that there are still some traditional mechanisms in these patients that may have been the cause of the stroke that may not have been fully elucidated, or if they were, were not reported in the paper. I see that patients 2 and 3 had atrial fibrillation, on warfarin, with supra-therapeutic (3.6, artificial heart valve) and sub-therapeutic (1.03) INRs respectively. The results of echocardiography and cardiac rhythm monitoring were not reported for any patient. Thus cardioembolism is still possible as a cause of stroke. Patients 2 to 5 had hypertension and at least one other atherosclerotic vascular risk factor (eg diabetes mellitus, hypercholesterolaemia, smoking, stroke). All patients save 1 was above 60 years of age. Vascular imaging was only reported for 2 cases (5 - CTA and 6 - MRA). Atherothromboelbolism may have caused stroke in some of the patients.

  I refer to case series of stroke seen during the 2002-2204 SARS epidemic, also due to a corona virus (2); all had large artery ischaemic strokes, at least 2 of 4 assessed patients had a cardioembolic source, with another having a recent myocardial infarction. I feel there is value in doing as full an evaluation as is reasonably possible to determine the cause of stroke.

  The TOAST criteria are widely used in clinical practice, classifying ischaemic stroke mechanisms into 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) stroke of other determined etiology, and 5) stroke of undetermined etiology (3). The last category includes those who had more than 1 determined cause, had no determined cause despite extensive investigation, or who had an incomplete aetiological evaluation. Thus, each case requires a full evaluation before cause is assigned; else they will be of undetermined origin.

  I hope the authors could kindly provide follow-up information on the results of these investigations, when they are available, so that we may better understand the cause of the stroke in all their patients.

  Thank you again for a most interesting paper.

  1. Beyrouti R, Adams ME, Benjamin L, Cohen H, Farmer SF, Goh YY, Humphries F,
  Jäger HR, Losseff NA, Perry RJ, Shah S, Simister RJ, Turner D, Chandratheva A,
  Werring DJ. Characteristics of ischaemic stroke associated with COVID-19. J
  Neurol Neurosurg Psychiatry. 2020 Apr 30. pii: jnnp-2020-323586
  2. Umapathi T, Kor AC, Venketasubramanian N, Lim CC, Pang BC, Yeo TT, Lee CC, Lim
  PL, Ponnudurai K, Chuah KL, Tan PH, Tai DY, Ang SP. Large artery ischaemic stroke
  in severe acute respiratory syndrome (SARS). J Neurol. 2004 Oct;251(10):1227-31.
  3. Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE
  3rd. Classification of subtype of acute ischemic stroke. Definitions for use in a
  multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.
  Stroke. 1993 Jan;24(1):35-41

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  Conflict of Interest:
  None declared.

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