Etiology

Ischemic stroke is caused by a transient or permanent critical reduction in cerebral blood flow due to arterial stenosis or occlusion. Identification of the underlying mechanisms and etiologies is important so that appropriate therapy can be initiated to decrease the risk of recurrent stroke.

Although it has limitations, the classification scheme for ischemic stroke developed for the Trial of Org 10172 in Acute Stroke Treatment (TOAST) is commonly used and provides a framework for determining the stroke mechanism, with implications for identifying the underlying etiology.​​​​[2]​[3] Other classification systems are available.[4][5][6]

Large artery atherosclerosis affects the extracranial carotid or vertebral arteries, or less commonly the major intracranial arteries, such as the middle cerebral artery.[24] It is a site for thrombus formation that then embolizes to distal sites and/or occludes the vessel.

Small vessel (lacunar) stroke is caused by thrombotic occlusion of a small penetrating artery affected by lipohyalinosis (lipid accumulation due to aging and hypertension), resulting in a <1.5-cm infarct in the perfusion territory of the affected small vessel.

Cardioembolism results from thrombus formation in the heart, which then embolizes to the intracranial circulation, and is associated with cardiac disease such as atrial fibrillation. Aortic atherosclerotic plaque is another potential source of thrombus formation with embolism.[25][26]

Strokes of other determined etiology may be caused by various diseases of the intracranial or extracranial vessels (e.g., vasospasm, dissection, vasculitis, venous thrombosis) or hematologic system (e.g., sickle cell anemia, polycythemia, antiphospholipid antibody syndrome, and other hypercoagulable states).

Strokes of undetermined etiology, despite complete workup, are not uncommon. In the Northern Manhattan Stroke Study, 32% of strokes had no identifiable etiology.[27]

Pathophysiology

Regardless of the etiology, ischemic stroke occurs when blood supply in a cerebral vascular territory is critically reduced due to occlusion or critical stenosis of a cerebral artery. A minority of ischemic strokes are caused by cerebral sinus or cortical vein thrombosis. These are frequently associated with a prothrombotic (hypercoagulable or hyperaggregable) state, with resulting venous insufficiency and reduced blood flow.

Pathophysiologically, ischemic stroke can be broadly classified as:

  • Primary vascular pathologies (e.g., atherosclerosis, vasospasm, arterial dissection, vasculitis) that directly reduce cerebral perfusion and/or result in artery-to-artery embolism (i.e., stenosis or occlusion of a distal artery by an embolus originating in a proximal artery)

  • Cardiac pathologies (e.g., atrial myxoma, atrial fibrillation, myocardial ischemia/infarction, patent foramen ovale, endocarditis) that lead to cerebral arterial occlusion due to embolism

  • Hematologic pathologies (e.g., prothrombotic hypercoagulable or hyperaggregable states) that directly precipitate cerebrovascular thrombosis (particularly venous), or facilitate systemic venous or intracardiac thrombus formation and cardioembolism.

Classification

There are several stroke classification systems, including Trial of Org 10172 in Acute Stroke Treatment (TOAST), Oxford Community Stroke Project classification system, A-S-C-O (phenotypic), and Chinese Ischemic Stroke Subclassification (CISS). TOAST is the most widely used system.

Trial of Org 10172 in Acute Stroke Treatment (TOAST criteria)[2]​​

Classify ischemic stroke according to pathophysiology:

Large artery atherosclerosis

  • Infarction in the perfusion territory of an extracranial or intracranial artery with more than 50% stenosis, and no other likely cause of stroke.

Cardioembolism

  • Infarction in the presence of at least one cardiac condition strongly associated with stroke, such as atrial fibrillation.

Small vessel occlusion

  • Infarction <1.5 cm in diameter in the perfusion territory of a small penetrating blood vessel.

Stroke of other determined etiology

  • Examples include cerebral infarction caused by vasculitis, arterial dissection, and hypercoagulable states.

Stroke of undetermined etiology

  • Infarction in the setting of two or more different potential etiologies, no potential etiology despite complete diagnostic evaluation, or an incomplete evaluation.

Causative classification of stroke modified TOAST criteria[3]

This web-based validated classification algorithm subtypes ischemic stroke according to pathophysiologic mechanism. Categories are:

  • Large artery atherosclerosis

  • Cardioaortic embolism

  • Small artery occlusion

  • Other causes

  • Undetermined causes.

Undetermined causes are divided into:

  • Unknown - embolic stroke of undetermined source

  • Unknown - multiple causes

  • Unknown - incomplete evaluation.

Each subtype except for the undetermined group is subdivided based on the weight of evidence as:

  • Evident

  • Probable

  • Possible.

Oxford Community Stroke Project classification system[4]

Subtypes ischemic stroke according to vascular territory of infarction:

  • Total anterior circulation infarction

  • Partial anterior circulation syndrome

  • Lacunar infarction

  • Posterior circulation infarction.

A-S-C-O (phenotypic) classification of stroke[5]

Each patient is characterized by A-S-C-O:

  • A: atherosclerosis

  • S: small vessel disease

  • C: cardioembolism

  • O: other cause.

Each of the four phenotypes is also graded 0, 1, 2, or 3 (or when grading is not possible due to insufficient workup, a grade of 9 is given):

  • 0: disease completely absent

  • 1: definitely a potential cause of the index stroke

  • 2: causality uncertain

  • 3: unlikely to be a direct cause of the index stroke, but disease is present.

For example, a patient with a normal carotid artery, lacunar stroke, no atrial fibrillation, and no hypercoagulable state is classified as A3-S1-C3-O3. A patient with no brain imaging, normal ECG, and normal cardiac imaging is classified as A3-S9-C3-O3.

Chinese Ischemic Stroke Subclassification (CISS)[6]

CISS is a two-step system that classifies stroke by etiology and then by underlying mechanism.

The first step classifies stroke into five categories:

  • Large artery atherosclerosis (LAA), including atherosclerosis of the aortic arch and intra-/extracranial large arteries

  • Cardiogenic stroke

  • Penetrating artery disease

  • Other etiology

  • Undetermined etiology.

The second step further classifies the underlying mechanism of ischemic stroke from intracranial or extracranial LAA into the following:

  • Parent artery (plaque or thrombosis) occluding penetrating artery

  • Artery-to-artery embolism

  • Hypoperfusion/impaired emboli clearance

  • Multiple mechanisms.

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