User:Gunnar Römer/sandbox

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. As such, it forms a subset of cryptogenetic stroke, which is part of the TOAST-classification. The following diagnostic criteria define an ESUS:


 * Stroke detected by CT or MRI that is not Lacunar stroke|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)

Cryptogenetic 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.

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. Patients with ESUS tend to be relatively young and experience mild strokes, however 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.

Potential causes of ESUS
The following factors are suggested as pathogenesis of ESUS:


 * 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 cryptogenetic stroke. Aortic arch atherosclerosis is believed to be a specific cause of ESUS, particularly with plaques >4 mm diameter.
 * 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%).

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. However, it is widely believed that there is a substantial overlap between ESUS and cardioembolic stroke so there may be a rationale for anticoagulation. 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).

NAVIGATE ESUS
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 7214 adults aged ≥50 years. The study was terminated in early October 2017.

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.

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. As such, it forms a subset of cryptogenetic stroke, which is part of the TOAST-classification. The following diagnostic criteria define an ESUS:


 * Stroke detected by CT or MRI that is not Lacunar stroke|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)

Cryptogenetic 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.

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. Patients with ESUS tend to be relatively young and experience mild strokes, however 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.

Potential causes of ESUS
The following factors are suggested as pathogenesis of ESUS:


 * 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 cryptogenetic stroke. Aortic arch atherosclerosis is believed to be a specific cause of ESUS, particularly with plaques >4 mm diameter.
 * 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%).

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. However, it is widely believed that there is a substantial overlap between ESUS and cardioembolic stroke so there may be a rationale for anticoagulation. 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).

NAVIGATE ESUS
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 7214 adults aged ≥50 years. The study was terminated in early October 2017.

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.