Embolic stroke of undetermined source

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

Cryptogenic stroke vs ESUS

Cryptogenic stroke is also an ischemic stroke with more than one probable cause or strokes with incomplete diagnostic workup.[2] 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.

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.[3] 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.[4][5]

Potential causes of ESUS

The following factors are suggested as pathogenesis of ESUS:[6]

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%).[1]

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.[10][11][12] However, it is widely believed that there is a substantial overlap between ESUS and cardioembolic stroke so there may be a rationale for anticoagulation.[1][13] This approach is currently tested in clinical trials.

Research

Currently, a number of studies for secondary prevention of stroke are under way to target ESUS.

RE-SPECT ESUS

In this multicentre, double blind, randomized, event-driven trial, 5390 adult patients (≥60 years of age or 18–59 years of age with at least one additional risk factor for stroke) with recent ESUS were randomized. Dabigatran (150 mg or 110 mg twice daily in patients ≥75 years or with moderate renal impairment) is being compared with ASA (100 mg once daily). The primary endpoint is time to first recurrent stroke (ischaemic, haemorrhagic, or unspecified).[14][15]

This multicentre, double-blind, randomized, event-driven trial appraises patients with recent ESUS, comparing rivaroxaban (15 mg once daily) with ASA (100 mg once daily) to prevent recurrent strokes and systemic embolism in patients aged ≥50 years. 3604 patients received aspirin and 3609 were treated with rivaroxaban, median follow-up was 11 months. The primary efficacy outcome occurred in 160 patients (annualized rate, 4.8%) treated with aspirin. This compares with 172 patients (annualized rate, 5.1%) in the rivaroxaban group. 23 patients in the aspirin arm suffered from major bleeding. In contrast, 62 patients treated with rivaroxaban had bleeding events. In the aspirin group, 156 patients had recurrent ischemic stroke compared with 158 patients in the rivaroxaban group. The study was terminated in early October 2017. In conclusion, rivaroxaban was not superior to aspirin in preventing recurrent stroke after an initial embolic stroke of undetermined source. In addition, rivaroxaban was associated with an increased risk of bleeding.[16][17][18][19]

ATTICUS

ATTICUS is a multicenter, blinded, open-label, randomized, event-driven trial of patients with recent ESUS, comparing apixaban (5 or 2.5 mg twice daily) with ASA (100 mg once daily) to prevent new ischaemic lesions in adults (aged ≥18 years). The study is aiming to include 500 patients who suffered ESUS within the past 7 days. The primary outcome is the occurrence of at least one new ischemic lesion detected by MRI imaging.[20][21]

References

  1. 1 2 3 4 Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O'Donnell MJ, Sacco RL, Connolly SJ (April 2014). "Embolic strokes of undetermined source: the case for a new clinical construct". The Lancet. Neurology. 13 (4): 429–38. doi:10.1016/S1474-4422(13)70310-7. PMID 24646875.
  2. 1 2 Adams HP, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE (January 1993). "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. doi:10.1161/01.STR.24.1.35. PMID 7678184.
  3. ↑ Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ (April 2017). "Embolic Stroke of Undetermined Source: A Systematic Review and Clinical Update". Stroke. 48 (4): 867–872. doi:10.1161/STROKEAHA.116.016414. PMID 28265016.
  4. ↑ Ntaios G, Papavasileiou V, Milionis H, Makaritsis K, Manios E, Spengos K, Michel P, Vemmos K (January 2015). "Embolic strokes of undetermined source in the Athens stroke registry: a descriptive analysis". Stroke. 46 (1): 176–81. doi:10.1161/STROKEAHA.114.007240. PMID 25378429.
  5. ↑ Ntaios G, Papavasileiou V, Milionis H, Makaritsis K, Vemmou A, Koroboki E, et al. (August 2015). "Embolic Strokes of Undetermined Source in the Athens Stroke Registry: An Outcome Analysis". Stroke. 46 (8): 2087–93. doi:10.1161/STROKEAHA.115.009334. PMID 26159795.
  6. 1 2 Nouh A, Hussain M, Mehta T, Yaghi S (2016). "Embolic Strokes of Unknown Source and Cryptogenic Stroke: Implications in Clinical Practice". Frontiers in Neurology. 7: 37. doi:10.3389/fneur.2016.00037. PMID 27047443.
  7. ↑ Freilinger TM, Schindler A, Schmidt C, Grimm J, Cyran C, Schwarz F, et al. (April 2012). "Prevalence of nonstenosing, complicated atherosclerotic plaques in cryptogenic stroke". JACC. Cardiovascular Imaging. 5 (4): 397–405. doi:10.1016/j.jcmg.2012.01.012. PMID 22498329.
  8. ↑ Gupta A, Gialdini G, Lerario MP, Baradaran H, Giambrone A, Navi BB, et al. (June 2015). "Magnetic resonance angiography detection of abnormal carotid artery plaque in patients with cryptogenic stroke". Journal of the American Heart Association. 4 (6): e002012. doi:10.1161/JAHA.115.002012. PMC 4599540. PMID 26077590.
  9. ↑ Amarenco P, Cohen A, Tzourio C, Bertrand B, Hommel M, Besson G, et al. (December 1994). "Atherosclerotic disease of the aortic arch and the risk of ischemic stroke". The New England Journal of Medicine. 331 (22): 1474–9. doi:10.1056/NEJM199412013312202. PMID 7969297.
  10. ↑ European Stroke Organisation (ESO) Executive Committee, Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, et al. (July 2014). "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. doi:10.1161/STR.0000000000000024. PMID 24788967.
  11. ↑ Lansberg MG, O'Donnell MJ, Khatri P, Lang ES, Nguyen-Huynh MN, Schwartz NE, et al. (February 2012). "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. doi:10.1378/chest.11-2302. PMC 3278065. PMID 22315273.
  12. ↑ European Stroke Organisation (ESO) Executive Committee; ESO Writing Committee, Ringleb PA, Bousser MG, Ford G, Bath P, Brainin M, et al. (2008). "Guidelines for management of ischaemic stroke and transient ischaemic attack 2008". Cerebrovascular Diseases. 25 (5): 457–507. doi:10.1159/000131083. PMID 18477843.
  13. ↑ Kamel H, Healey JS (February 2017). "Cardioembolic Stroke". Circulation Research. 120 (3): 514–526. doi:10.1161/CIRCRESAHA.116.308407. PMC 5312810. PMID 28154101.
  14. ↑ Diener HC, Easton JD, Granger CB, Cronin L, Duffy C, Cotton D, et al. (December 2015). "Design of Randomized, double-blind, Evaluation in secondary Stroke Prevention comparing the EfficaCy and safety of the oral Thrombin inhibitor dabigatran etexilate vs. acetylsalicylic acid in patients with Embolic Stroke of Undetermined Source (RE-SPECT ESUS)". International Journal of Stroke. 10 (8): 1309–12. doi:10.1111/ijs.12630. PMID 26420134.
  15. ↑ Clinical trial number NCT02239120 for "Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source (RE-SPECT ESUS)" at ClinicalTrials.gov
  16. ↑ Hart RG, Sharma M, Mundl H, Shoamanesh A, Kasner SE, Berkowitz SD, Pare G, Kirsch B, et al. (2016). "Rivaroxaban for secondary stroke prevention in patients with embolic strokes of undetermined source: Design of the NAVIGATE ESUS randomized trial". European Stroke Journal. 1 (3): 146–54. doi:10.1177/2396987316663049.
  17. ↑ Clinical trial number NCT02313909 for "Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source (ESUS) (NAVIGATE ESUS)" at ClinicalTrials.gov
  18. ↑ Press release Bayer AG: Bayer´s NAVIGATE ESUS study halted early as indicated efficacy between treatment arms.
  19. ↑ Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, et al. (May 2018). "Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source". The New England Journal of Medicine. doi:10.1056/NEJMoa1802686. PMID 29766772.
  20. ↑ Geisler T, Poli S, Meisner C, Schreieck J, Zuern CS, Nägele T, et al. (December 2017). "Apixaban for treatment of embolic stroke of undetermined source (ATTICUS randomized trial): Rationale and study design". International Journal of Stroke. 12 (9): 985–990. doi:10.1177/1747493016681019. PMID 27881833.
  21. ↑ Clinical trial number NCT02427126 for "Apixaban for Treatment of Embolic Stroke of Undetermined Source (ATTICUS)" at ClinicalTrials.gov

Further reading

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