by Dr Gerrit M Grosse, Department of Neurology, Hannover Medical School, Hannover, Germany

After both the RE-SPECT ESUS1 and NAVIGATE ESUS2 study results remained neutral we are still in need of clarifying the most likely mechanism of stroke origin in patients who suffered an embolic stroke of undetermined source (ESUS).

A growing body of evidence exists that nonstenotic carotid plaque is found frequently ipsilateral to the affected brain territory in ESUS.3,4 Carotid plaque thickness was repeatedly reported to be greater ipsilateral to the infarction compared with the contralateral side in ESUS-patients.5,6  In contrast, this association was not observed in patients with stroke due to atrial fibrillation (AF).7

Recently, Kopczak et al. published results from the CAPIAS study, in which 234 patients with acute ischaemic stroke underwent high-resolution contrast-enhanced carotid MRI in order to characterize nonstenotic carotid plaques according to the modified AHA criteria.8 The colleagues were able to show a higher prevalence of complicated (AHA lesion type VI) carotid plaques ipsilateral to the infarction (31%) compared with the contralateral side (12%)  in patients with cryptogenic stroke.8 Moreover, these complicated carotid plaques were also less frequent in patients with cardioembolic or small vessel stroke (15%).8

In conclusion, these studies reinforce the hypothesis of nonstenotic carotid plaques as potential embolic source in cryptogenic stroke. However, potentially competing etiologies, such as paroxysmal AF, should not be neglected either. Atherosclerosis and AF share vascular risk factors and feature pathophysiological coherencies.9 In accordance with these considerations, large samples of the general population repeatedly revealed a strong association between systemic and specifically carotid atherosclerosis with AF.10,11 The relation between nonstenotic carotid plaques, even with high-risk plaque features, and atrial cardiopathy also applies to patients who have suffered ESUS.12 To that extent, we should not forget to continue screening for AF and atrial cardiopathy in ESUS patients, in particular in those with manifest atherosclerosis. Moreover, other potential embolic sources include left ventricular disease, heart valve anomalies, patent foramen ovale or coagulation disorders and it has been shown that a majority of ESUS patients may exhibit multiple potential stroke etiologies at once.13,14

Therefore, it will be exciting to see what kind of future strategies will emerge to support the diagnosis of the actual stroke mechanism. For now, it remains apparent that a dedicated and thorough neurovascular assessment is required to optimize the secondary preventive approach of patients who suffered cryptogenic stroke. Evaluating nonstenotic carotid plaques may be a helpful step in this process.


1 Diener, H. C. et al. Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source. The New England journal of medicine 380, 1906-1917, doi:10.1056/NEJMoa1813959 (2019).

2 Hart, R. G. et al. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. The New England journal of medicine 378, 2191-2201, doi:10.1056/NEJMoa1802686 (2018).

3 Ntaios, G., Wintermark, M. & Michel, P. Supracardiac atherosclerosis in embolic stroke of undetermined source: the underestimated source. Eur Heart J, doi:10.1093/eurheartj/ehaa218 (2020).

4 Ospel, J. M. et al. Prevalence of Ipsilateral Nonstenotic Carotid Plaques on Computed Tomography Angiography in Embolic Stroke of Undetermined Source. Stroke 51, 1743-1749, doi:10.1161/strokeaha.120.029404 (2020).

5 Komatsu, T. et al. Large but Nonstenotic Carotid Artery Plaque in Patients With a History of Embolic Stroke of Undetermined Source. Stroke 49, 3054-3056, doi:10.1161/strokeaha.118.022986 (2018).

6 Siegler, J. E. et al. Prevalence of Nonstenotic Carotid Plaque in Stroke Due to Atrial Fibrillation Compared to Embolic Stroke of Undetermined Source. J Stroke Cerebrovasc Dis 28, 104289, doi:10.1016/j.jstrokecerebrovasdis.2019.07.005 (2019).

7 Knight‐Greenfield, A. et al. Associations Between Features of Nonstenosing Carotid Plaque on Computed Tomographic Angiography and Ischemic Stroke Subtypes. Journal of the American Heart Association 8, e014818, doi:doi:10.1161/JAHA.119.014818 (2019).

8 Kopczak, A. et al. Complicated Carotid Artery Plaques as a Cause of Cryptogenic Stroke. Journal of the American College of Cardiology 76, 2212-2222, doi:doi:10.1016/j.jacc.2020.09.532 (2020).

9 Willeit, K. & Kiechl, S. Atherosclerosis and atrial fibrillation–two closely intertwined diseases. Atherosclerosis 233, 679-681, doi:10.1016/j.atherosclerosis.2013.11.082 (2014).

10 Wang, Z., Korantzopoulos, P. & Liu, T. Carotid Atherosclerosis in Patients with Atrial Fibrillation. Current Atherosclerosis Reports 21, 55, doi:10.1007/s11883-019-0808-4 (2019).

11 Heeringa, J. et al. Subclinical atherosclerosis and risk of atrial fibrillation: the rotterdam study. Archives of internal medicine 167, 382-387, doi:10.1001/archinte.167.4.382 (2007).

12 Grosse, G. M. et al. Nonstenotic Carotid Plaque in Embolic Stroke of Undetermined Source: Interplay of Arterial and Atrial Disease. Stroke 51, 3737-3741, doi:10.1161/strokeaha.120.030537 (2020).

13 Ntaios, G. et al. Prevalence and Overlap of Potential Embolic Sources in Patients With Embolic Stroke of Undetermined Source. Journal of the American Heart Association 8, e012858, doi:doi:10.1161/JAHA.119.012858 (2019).

14  Ntaios, G. et al. Potential Embolic Sources and Outcomes in Embolic Stroke of Undetermined Source in the NAVIGATE-ESUS Trial. Stroke 51, 1797-1804, doi:doi:10.1161/STROKEAHA.119.028669 (2020).