Embolic stroke of undetermined source explained

Embolic stroke of undetermined source (ESUS) is an embolic stroke, a type of ischemic stroke, with an unknown origin,^[1] defined as a non-lacunar brain infarct without proximal arterial stenosis or cardioembolic sources.^[2] As such, it forms a subset of cryptogenic stroke, which is part of the TOAST-classification.^[3] The following diagnostic criteria define an ESUS:

• Stroke detected by CT or MRI that is not lacunar
• No major-risk cardioembolic source of embolism
• Absence of extracranial or intracranial atherosclerosis causing 50% luminal stenosis in arteries supplying the area of ischaemia
• No other specific cause of stroke identified (e.g., arteritis, dissection, migraine/vasospasm, drug misuse)

Causes

The following factors are suggested as pathogenesis of ESUS:^[4]

• Subclinical atrial fibrillation: Detectable in ~2.7-30% of ESUS patients, depending on duration and modality of ECG monitoring.
• Patent foramen ovale (PFO): Deep vein thrombosis may result in paradoxical embolism in patients with PFO. About 40% of patients with cryptogenic stroke have PFO compared with 25% of the general population. However, the actual embolic source can often not be identified.
• Non-stenotic arterial plaques: Complicated plaques with signs indicative of intra-plaque haemorrhage in an ipsilateral carotid artery are detected in 1 in 4 of patients with cryptogenic stroke.^{[5] [6]} Aortic arch atherosclerosis is believed to be a specific cause of ESUS, particularly with plaques >4 mm diameter.^[7]
• Further cardiopathies: the risk of ischaemic stroke is increased by supraventricular tachycardias. This also applies to patients with elevated NT-proBNP levels and patients with atrial enlargement in cardiac ultrasound.
• Other causes: Arterial dissections, infection-related vasculopathies (esp. Varicella zoster virus), thrombophilia, cancer-related thrombosis, migraine, Fabry disease and other genetic, autoimmune or rheumatic causes.

Diagnosis

ESUS is a diagnosis of exclusion based on radiological and cardiological examinations. For exclusion of haemorrhagic or lacunar strokes CT or MRI imaging is needed. Both procedures also allow detection of embolic pattern of ischemic lesions. 12-lead ECG and cardiac monitoring for at least 24 h with automated rhythm detection are mandated to exclude atrial fibrillation; echocardiography (TTE and/or TEE) is used to detect other major-risk cardioembolic sources (e.g., intracardiac thrombi, or ejection fraction <30%). For imaging of both the extracranial and intracranial arteries supplying the area of brain ischaemia, examination methods like catheter, MR/CT angiography or cervical duplex plus transcranial Doppler ultrasonography are required. They allow an exclusion of large vessel stenosis (≥ 50%).

Cryptogenic stroke vs ESUS

Cryptogenic stroke is also an ischemic stroke with more than one probable cause or strokes with incomplete diagnostic workup. ESUS has a clearer definition, with an established minimum diagnostic requirements; this is not required in defining a cryptogenic stroke. ESUS is an embolic stroke for which no probable cause can be identified after a standard diagnostic evaluation.

Management

Due to the lack of data, there are no specific treatment guidelines for ESUS. Current guidelines recommend antiplatelet therapy for patients with non-cardioembolic ischemic stroke.^{[8] [9] [10]} However, it is widely believed that there is a substantial overlap between ESUS and cardioembolic stroke, clinical trials have assessed the benefit of anticoagulation versus antiplatelet agents for preventing recurrent stroke.^[11] Although the existing data does not favor the use anticoagulation in patients with ESUS, current hypotheses suggest there may be subgroups who do benefit from anticoagulation.^[12]

Epidemiology

On average, ESUS accounts for about 1 in 6 ischemic strokes (17% (range 9 – 25%)) according to a systematic literature review of 9 studies.^[13] Patients with ESUS tend to be relatively young and experience mild strokes. However, ESUS is associated with high recurrence rates. Of 2045 ESUS patients (identified by 8 studies)

• 58% were male,
• the mean age was 65 years,
• the average annualized rate of stroke recurrence was 4.5%
• mean NIHSS at stroke onset was 5.

The stroke recurrence rate was 29.0% over 5 years in patients with ESUS, which is similar to patients with cardioembolic stroke (26.8%), but significantly higher than all types of non-cardioembolic stroke. However, mortality was significantly lower in patients with ESUS than cardioembolic stroke.^{[14] [15]}

Further reading

• Spence JD . Cryptogenic Stroke . The New England Journal of Medicine . 375 . 11 . e26 . September 2016 . 27626543 . 10.1056/NEJMc1609156 .
• Amin H, Greer DM . Cryptogenic stroke-the appropriate diagnostic evaluation . Current Treatment Options in Cardiovascular Medicine . 16 . 1 . 280 . January 2014 . 24352977 . 10.1007/s11936-013-0280-3 . 5528303 .
• Diener HC, Bernstein R, Hart R . Secondary Stroke Prevention in Cryptogenic Stroke and Embolic Stroke of Undetermined Source (ESUS) . Current Neurology and Neuroscience Reports . 17 . 9 . 64 . September 2017 . 28707135 . 10.1007/s11910-017-0775-5 . 207334933 .

Notes and References

1. Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ . Embolic Stroke of Undetermined Source: A Systematic Review and Clinical Update . Stroke . 48 . 4 . 867–872 . April 2017 . 28265016 . 10.1161/STROKEAHA.116.016414 . 3679562 . free .
2. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O'Donnell MJ, Sacco RL, Connolly SJ . Embolic strokes of undetermined source: the case for a new clinical construct . The Lancet. Neurology . 13 . 4 . 429–38 . April 2014 . 24646875 . 10.1016/S1474-4422(13)70310-7 . 36116833 .
3. Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE . 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 . 24 . 1 . 35–41 . January 1993 . 7678184 . 10.1161/01.STR.24.1.35 . free .
4. Nouh A, Hussain M, Mehta T, Yaghi S . Embolic Strokes of Unknown Source and Cryptogenic Stroke: Implications in Clinical Practice . Frontiers in Neurology . 7 . 37 . 2016 . 27047443 . 4800279 . 10.3389/fneur.2016.00037 . free .
5. Freilinger TM, Schindler A, Schmidt C, Grimm J, Cyran C, Schwarz F, Bamberg F, Linn J, Reiser M, Yuan C, Nikolaou K, Dichgans M, Saam T . 6 . Prevalence of nonstenosing, complicated atherosclerotic plaques in cryptogenic stroke . JACC: Cardiovascular Imaging . 5 . 4 . 397–405 . April 2012 . 22498329 . 10.1016/j.jcmg.2012.01.012 . free .
6. Gupta A, Gialdini G, Lerario MP, Baradaran H, Giambrone A, Navi BB, Marshall RS, Iadecola C, Kamel H . 6 . Magnetic resonance angiography detection of abnormal carotid artery plaque in patients with cryptogenic stroke . Journal of the American Heart Association . 4 . 6 . e002012 . June 2015 . 26077590 . 4599540 . 10.1161/JAHA.115.002012 .
7. Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G, Chauvel C, Touboul PJ, Bousser MG . 6 . Atherosclerotic disease of the aortic arch and the risk of ischemic stroke . The New England Journal of Medicine . 331 . 22 . 1474–9 . December 1994 . 7969297 . 10.1056/NEJM199412013312202 . free .
8. ((European Stroke Organisation (ESO) Executive Committee)), Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, Fang MC, Fisher M, Furie KL, Heck DV, Johnston SC, Kasner SE, Kittner SJ, Mitchell PH, Rich MW, Richardson D, Schwamm LH, Wilson JA . 6 . Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association . Stroke . 45 . 7 . 2160–236 . July 2014 . 24788967 . 10.1161/STR.0000000000000024 . free .
9. Lansberg MG, O'Donnell MJ, Khatri P, Lang ES, Nguyen-Huynh MN, Schwartz NE, Sonnenberg FA, Schulman S, Vandvik PO, Spencer FA, Alonso-Coello P, Guyatt GH, Akl EA . 6 . Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines . Chest . 141 . 2 Suppl . e601S–e636S . February 2012 . 22315273 . 3278065 . 10.1378/chest.11-2302 .
10. ((European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee)), Ringleb PA, Bousser MG, Ford G, Bath P, Brainin M, Caso V, Cervera A, Chamorro A, Cordonnier C, Csiba L, Davalos A, Diener HC, Ferro J, Hacke W, Hennerici M, Kaste M, Langhorne P, Lees K, Leys D, Lodder J, Markus HS, Mas JL, Mattle HP, Muir K, Norrving B, Obach V, Paolucci S, Ringelstein EB, Schellinger PD, Sivenius J, Skvortsova V, Sunnerhagen KS, Thomassen L, Toni D, von Kummer R, Wahlgren NG, Walker MF, Wardlaw J . 6 . Guidelines for management of ischaemic stroke and transient ischaemic attack 2008 . Cerebrovascular Diseases . 25 . 5 . 457–507 . 2008 . 18477843 . 10.1159/000131083 . free .
11. Kamel H, Healey JS . Cardioembolic Stroke . Circulation Research . 120 . 3 . 514–526 . February 2017 . 28154101 . 5312810 . 10.1161/CIRCRESAHA.116.308407 .
12. Greeve . Isabell . Schäbitz . Wolf-Rüdiger . May 2022 . Embolic stroke of undetermined source: identification of patient subgroups for oral anticoagulation treatment . Neural Regeneration Research . 17 . 5 . 1005–1006 . 10.4103/1673-5374.324837 . 1673-5374 . 8552842 . 34558521 . free .
13. Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ . Embolic Stroke of Undetermined Source: A Systematic Review and Clinical Update . Stroke . 48 . 4 . 867–872 . April 2017 . 28265016 . 10.1161/STROKEAHA.116.016414 . free .
14. Ntaios G, Papavasileiou V, Milionis H, Makaritsis K, Manios E, Spengos K, Michel P, Vemmos K . Embolic strokes of undetermined source in the Athens stroke registry: a descriptive analysis . Stroke . 46 . 1 . 176–81 . January 2015 . 25378429 . 10.1161/STROKEAHA.114.007240 . free .
15. Ntaios G, Papavasileiou V, Milionis H, Makaritsis K, Vemmou A, Koroboki E, Manios E, Spengos K, Michel P, Vemmos K . 6 . Embolic Strokes of Undetermined Source in the Athens Stroke Registry: An Outcome Analysis . Stroke . 46 . 8 . 2087–93 . August 2015 . 26159795 . 10.1161/STROKEAHA.115.009334 . 1486434 .