Embolic stroke of undetermined source (ESUS) is a type of

ischemic stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...

with an unknown origin, defined as a non- lacunar brain infarct without proximal

arterial An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pul ...

stenosis A stenosis (from Ancient Greek στενός, "narrow") is an abnormal narrowing in a blood vessel or other tubular organ or structure such as foramina and canals. It is also sometimes called a stricture (as in urethral stricture). ''Stricture'' ...

or cardioembolic sources. As such, it forms a subset of cryptogenic stroke, which is part of the TOAST-classification. The following diagnostic criteria define an ESUS: * Stroke detected by CT or

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

that is not lacunar * No major-risk cardioembolic source of

embolism An embolism is the lodging of an embolus, a blockage-causing piece of material, inside a blood vessel. The embolus may be a blood clot (thrombus), a fat globule ( fat embolism), a bubble of air or other gas (gas embolism), amniotic fluid (amniot ...

* Absence of extracranial or intracranial

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...

causing 50% luminal stenosis in arteries supplying the area of

ischaemia Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

* No other specific cause of stroke identified (e.g.,

arteritis Arteritis is the inflammation of the walls of arteries, usually as a result of infection or autoimmune response. Arteritis, a complex disorder, is still not entirely understood. Arteritis may be distinguished by its different types, based on the o ...

dissection Dissection (from Latin ' "to cut to pieces"; also called anatomization) is the dismembering of the body of a deceased animal or plant to study its anatomical structure. Autopsy is used in pathology and forensic medicine to determine the cause o ...

migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

vasospasm Vasospasm refers to a condition in which an arterial spasm leads to vasoconstriction. This can lead to tissue ischemia and tissue death (necrosis). Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or de ...

drug misuse Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...

)

Signs and symptoms

Causes

The following factors are suggested as

pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...

of ESUS: *

Subclinical In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asym ...

atrial fibrillation: Detectable in ~2.7-30% of ESUS patients, depending on duration and modality of ECG monitoring. *

Patent foramen ovale Atrial septal defect (ASD) is a congenital heart defect in which blood flows between the atria (upper chambers) of the heart. Some flow is a normal condition both pre-birth and immediately post-birth via the foramen ovale; however, when this d ...

(PFO):

Deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enla ...

may result in

paradoxical embolism An embolus, is described as a free-floating mass, located inside blood vessels that can travel from one site in the blood stream to another. An embolus can be made up of solid (like a blood clot), liquid (like amniotic fluid), or gas (like air). O ...

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 Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vagi ...

in an

ipsilateral Standard anatomical terms of location are used to unambiguously describe the anatomy of animals, including humans. The terms, typically derived from Latin or Greek roots, describe something in its standard anatomical position. This position pro ...

carotid artery Carotid artery may refer to: * Common carotid artery, often "carotids" or "carotid", an artery on each side of the neck which divides into the external carotid artery and internal carotid artery * External carotid artery, an artery on each side of t ...

are detected in 1 in 4 of patients with cryptogenic stroke.

Aortic arch The aortic arch, arch of the aorta, or transverse aortic arch () is the part of the aorta between the ascending and descending aorta. The arch travels backward, so that it ultimately runs to the left of the trachea. Structure The aorta begins a ...

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 tachycardia Supraventricular tachycardia (SVT) is an umbrella term for fast heart rhythms arising from the upper part of the heart. This is in contrast to the other group of fast heart rhythms – ventricular tachycardia, which start within the lower cham ...

s. This also applies to patients with elevated NT-proBNP levels and patients with

atrial enlargement Atrial enlargement refers to a condition where the left atrium or right atrium of the heart is larger than would be expected. It can also affect both atria. Types include: * Left atrial enlargement * Right atrial enlargement References

Ca ...

in cardiac ultrasound. * Other causes: Arterial dissections,

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dise ...

-related vasculopathies (esp.

Varicella zoster virus Varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3, HHV3) or ''Human alphaherpesvirus 3'' (taxonomically), is one of nine known herpes viruses that can infect humans. It causes chickenpox (varicella) commonly affecting chil ...

thrombophilia Thrombophilia (sometimes called hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels). Such abnormalities can be identified in 50% of people who ...

cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...

-related thrombosis, migraine,

Fabry disease Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. T ...

and other genetic,

autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". P ...

rheumatic Rheumatology (Greek ''ῥεῦμα'', ''rheûma'', flowing current) is a branch of medicine devoted to the diagnosis and management of disorders whose common feature is inflammation in the bones, muscles, joints, and internal organs. Rheumatolog ...

causes.

Diagnosis

ESUS is a

diagnosis of exclusion A diagnosis of exclusion or by exclusion (''per exclusionem'') is a diagnosis of a medical condition reached by a process of elimination, which may be necessary if presence cannot be established with complete confidence from history, examination or ...

based on

radiological In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or through a material medium. This includes: * ''electromagnetic radiation'', such as radio waves, microwaves, infrared, visib ...

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 An ejection fraction (EF) is the volumetric fraction (or portion of the total) of fluid (usually blood) ejected from a chamber (usually the heart) with each contraction (or heartbeat). It can refer to the cardiac atrium, ventricle, gall bladder, ...

<30%). For imaging of both the extracranial and intracranial arteries supplying the area of brain ischaemia, examination methods like

catheter In medicine, a catheter (/ˈkæθətər/) is a thin tube made from medical grade materials serving a broad range of functions. Catheters are medical devices that can be inserted in the body to treat diseases or perform a surgical procedure. Cath ...

, MR/CT angiography or cervical duplex plus transcranial

Doppler ultrasonography Doppler ultrasonography is medical ultrasonography that employs the Doppler effect to perform imaging of the movement of tissues and body fluids (usually blood), and their relative velocity to the probe. By calculating the frequency shift of ...

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 ''The Medical Letter on Drugs and Therapeutics'' (commonly referred to as ''The Medical Letter'') is a peer-reviewed biweekly medical journal providing evaluations of pharmaceutical drugs. It is published in English, French, and Italian. The jou ...

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 Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where the ...

. This approach is currently tested in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

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.

Patient A patient is any recipient of health care services that are performed by healthcare professionals. The patient is most often ill or injured and in need of treatment by a physician, nurse, optometrist, dentist, veterinarian, or other health c ...

s with ESUS tend to be relatively young and experience mild strokes. However, ESUS is associated with high

recurrence Recurrence and recurrent may refer to: *''Disease recurrence'', also called relapse *''Eternal recurrence'', or eternal return, the concept that the universe has been recurring, and will continue to recur, in a self-similar form an infinite number ...

rates. Of 2045 ESUS patients (identified by 8 studies) * 58% were

male Male (symbol: ♂) is the sex of an organism that produces the gamete (sex cell) known as sperm, which fuses with the larger female gamete, or ovum, in the process of fertilization. A male organism cannot reproduce sexually without access to ...

, * the mean age was 65 years, * the average annualized rate of stroke recurrence was 4.5% * mean

NIHSS The National Institutes of Health Stroke Scale, or NIH Stroke Scale (NIHSS), is a tool used by healthcare providers to objectively quantify the impairment caused by a stroke. The NIHSS is composed of 11 items, each of which scores a specific ability ...

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 Mortality is the state of being mortal, or susceptible to death; the opposite of immortality. Mortality may also refer to: * Fish mortality, a parameter used in fisheries population dynamics to account for the loss of fish in a fish stock throug ...

was significantly lower in patients with ESUS than cardioembolic stroke.