Proper clinical staging of acute ischemic stroke is essential for the acute treatment of patients, secondary prevention, and stroke-related research such as clinical trials, epidemiology, and genetics. Currently, the most widely used stroke staging system in clinical trials and clinical practice is the TOAST staging, which follows concepts derived mainly from the Harvard Stroke Registry staging and the National Institute of Neurological Disorders and Stroke Database staging criteria. Recently, two new stroke staging criteria have been published: the SSS-TOAST and the Korean modified TOAST staging, both of which improve and optimize the diagnostic criteria for atherosclerosis and small artery occlusion based on the original TOAST staging. The recently published A-S-C-O typing is more suitable for secondary prevention, clinical trials, and genetic-related studies. However, all of these typologies ignore penetrating atherosclerotic disease, and none of them further classify the pathophysiological mechanisms of ischemic stroke due to large artery atherosclerosis. In clinical work, we see patients with isolated foci of infarction in the penetrating arteries, not necessarily larger than 1.5 cm in diameter, and no stenosis in the carrier artery on angiography, but such patients are classified as small artery occlusion, small artery disease, or small vessel disease using existing classifications, and most modern neurologists usually consider this to be caused by small artery vitreous lesions, which obviously does not fit the clinical course of the disease. This is clearly not consistent with the clinical course of the disease, and such patients may not be effective despite the application of antiplatelet agents or anticoagulants, and the disease often progresses.
Such clinical manifestations compel one to think that perhaps the lesions at the mouth of the penetrating artery are still related, and our previous staging is lacking in this regard. 1 With the advent of imaging techniques such as 64-row CT, enhanced MRA (CEMRA), CT angiography (CTA), perfusion CT, magnetic resonance perfusion imaging (DWP), high-resolution MRI/MRA (HR-MRI/MRA), TCD microembolus monitoring (TCD-MES), transesophageal ultrasound (TEE), and cardiac magnetic resonance imaging, it has become possible to an increasing number of previously invisible pathological structures and ambiguous lesions can be clearly visualized. Here we present a new diagnostic standard for stroke staging – the Chinese ischemic stroke subtype (CISS).
CISS definition
In large artery atherosclerosis (LAA) CISS staging, large artery atherosclerosis (LAA) includes aortic arch and intracranial/extracranial large artery atherosclerosis.
1.Aortic arch atherosclerosis
2, acute multiple infarct lesions, especially involving bilateral anterior circulation and/or anterior-posterior circulation simultaneously
3. absence of corresponding intracranial or extracranial evidence of atherosclerotic lesions (vulnerable plaques or stenosis ≥50%) in the large arteries
4. no evidence of an underlying cause of cardiogenic stroke (CS)
5) no evidence of other etiologies that can cause acute multiple foci of infarction such as vasculitis, coagulation abnormalities, and tumor embolism; 5) evidence of aortic arch atherosclerosis of underlying etiology (aortic arch plaque ≥4 mm and/or surface thrombus confirmed by high-resolution MRI/MRA and/or transesophageal ultrasound).
2.Intracranial and extracranial large artery atherosclerosis
1, regardless of the type of infarct focus (except isolated infarct focus in the penetrating artery region), there was evidence of corresponding intracranial or extracranial large artery atherosclerosis (vulnerable plaque or stenosis ≥50%).
2. For the type of isolated infarct in the area of the penetrating 2 arteries, the following cases are also classified: atherosclerotic plaque (HR-MRI) or any degree of atherosclerotic stenosis (TCD, MRA, CTA or DSA) in the carrier artery.
3. the need to exclude cardiogenic stroke
4. Exclude other possible causes.
Diagnostic criteria for cardiogenic stroke (CS).
1. acute multiple foci of infarction, especially those involving bilateral anterior or anterior-posterior circulation coexisting in close temporal proximity, including the cortex
2, absence of corresponding intracranial and extracranial evidence of atherosclerosis in large arteries.
3. the absence of other causes capable of causing acute multiple infarct foci, such as vasculitis, coagulation system disease, tumor embolism, etc.
4. evidence of cardiogenic stroke.
5. Definite cardiogenic if atherosclerosis of the aortic arch is ruled out, or considered as possible cardiogenic if it cannot be ruled out. Potential causes of cardiogenic stroke include: mitral stenosis, heart valve replacement, myocardial infarction within the previous 4 weeks, left ventricular appendage thrombus, left ventricular wall tumor, any documented permanent or paroxysmal atrial fibrillation or atrial flutter, with or without spontaneous ultrasound imaging or left atrial emboli, sick sinus syndrome, dilated cardiomyopathy, ejection fraction <35%, endocarditis, intracardiac masses, oval or circular foramen ovale with in situ thrombus PFO, PFO with pulmonary embolism or deep vein thrombosis prior to the onset of cerebral infarction
Penetrating artery disease (PAD)
Acute isolated foci of infarction in the area of the penetrating artery due to atherosclerosis at the mouth of the penetrating artery or fibrous glassy changes in small arteries are called penetrating artery disease.
Diagnostic criteria.
1. acute isolated foci of infarction occurring in the zone of the penetrating artery consistent with clinical symptoms, irrespective of the size of the infarct.
2, absence of atherosclerotic plaque (HR-MRI) or any degree of stenosis (TCD, MRA, CTA or DSA) in the carrier artery.
3. ipsilateral proximal intracranial or extracranial artery with vulnerable plaque or >50% stenosis, with acute infarct foci in isolated penetrating arteries classified as of unknown origin (multi-cause)
4. isolated penetrating arterial zone infarct foci with evidence of cardiogenic embolism classified to unknown cause (multiple etiology).
5. other etiologies were excluded.
Other etiology (OE)
Presence of evidence of other specific diseases (e.g., vascular-related diseases, infectious diseases, genetic diseases, hematologic diseases, vasculitis, etc.) that are associated with the current stroke and can be confirmed by hematologic tests, cerebrospinal fluid (CSF) tests, and vascular imaging, while excluding the possibility of large artery atherosclerosis or cardiogenic stroke.
Uncertainty of etiology (UE)
No etiology was found that could explain this ischemic stroke. Multiple etiology: Two or more etiologies are found, but it is difficult to determine which one is associated with the stroke No definite etiology: No definite etiology is found, or there is a suspected etiology but the evidence is not strong enough unless further in-depth investigations are performed. Lack of examination: Routine vascular imaging or cardiac examination has not been completed, making it difficult to determine the cause.
Definition of potential pathophysiologic mechanisms of intracranial and extracranial large artery atherosclerotic ischemic stroke staging – Step 2 In the CISS staging system, the potential pathogenesis of intracranial and extracranial large artery atherosclerosis-induced ischemic stroke is further classified and defined as follows: obstruction of a penetrating artery by a carrier artery (plaque or thrombus), arterial-arterial embolism, decreased hypoperfusion/embolus clearance, and mixed mechanisms.
1. Carrier artery (plaque or thrombus) obstruction of a penetrating artery: acute isolated foci of infarction in the distribution area of a penetrating artery with evidence of plaque or any degree of stenosis in the carrier artery. For example, an acute isolated infarct foci occurring in the basal ganglia without other acute infarct foci in the ipsilateral MCA distribution; or an acute isolated infarct foci occurring in the cerebral bridge without other acute infarct foci in the basilar artery supply area. The acute isolated infarct foci are presumed to be caused by a plaque protruding from the carrier artery and blocking the blood flow in the penetrating artery.
2. Arterial-arterial embolism: Imaging shows small cortical foci of infarction or single regional foci of infarction within the distribution of atherosclerotic intracranial and extracranial large arteries. There is no watershed zone infarct associated with this lesion within its vascular distribution. The diagnosis is clear if the lesions are multiple or if a single infarcted lesion is present but a microembolic signal is found on TCD. However, arterial-arterial embolism can be diagnosed even if the cortical infarct is single or if there is a watershed infarct but no microembolic signal is found on TCD.
3. Hypoperfusion/decreased embolic clearance: Infarct lesions of this mechanism are located only in the watershed area. There are no acute cortical infarct foci or regional infarct foci within the vascular distribution of the lesion. The degree of intracranial or extracranial stenosis corresponding to clinical symptoms is usually >70%, with or without evidence of hypoperfusion or poor collateral compensation.
4. Mixed mechanisms: 2 or more of the above mechanisms are present simultaneously.
Description of etiologic staging
CISS classifies ischemic stroke aetiology into five types: LAA, CS, PAD, OE and UE. Compared with the previous classification, CISS has the following differences: aortic arch atherosclerosis is included in the large artery atherosclerotic type. Neither the classic TOAST nor the Korean version of TOAST mentions aortic arch atherosclerosis, and the SSS-TOAST classifies it as cardiogenic stroke. Although the type of infarct focus caused by atherosclerotic lesions in the aortic arch is closer to that of cardiac stroke, and it is easier to classify it as cardiac stroke from operational considerations, the lesion is atherosclerotic, and classification as atherosclerosis should be more reasonable.
In the atherosclerotic type of large artery, if the lesion is an isolated infarct focus in a penetrating artery, the carrier artery is classified as atherosclerotic as long as it has atherosclerotic plaque or any degree of stenosis, rather than requiring >50% stenosis or evidence of vulnerable plaque. This avoids classifying some infarcts caused by plaques with less than 50% stenosis blocking a penetrating branch as penetrating artery disease. In the etiologic diagnosis, a new name “penetrating artery disease” has been proposed, and the diagnostic criteria are very simple, with no requirement for infarct diameter or clinical manifestations of “luminal infarct syndrome”, excluding other diseases and considering isolated lesions of the penetrating artery itself Isolated foci of infarction in the area of the penetrating artery were considered to be caused by the lesion of the penetrating artery itself. The pathology of the penetrating artery showed that the main pathology of the penetrating artery itself leading to symptomatic infarcts was atheromatous lesions at the mouth of the penetrating artery, whereas the pathology of the penetrating artery leading to asymptomatic luminal or diffuse white matter laxity was mainly lipid vitreous lesions in the small terminal arteries. Most investigators have either studied only the carrier arteries (where atheromatous lesions were found) or only the terminal arteries (where fibrous vitreous lesions were found), and atheromatous lesions at the mouth of the penetrating arteries remain a neglected lesion that has been studied. Although there is no counter evidence that fibrous glassy lesions do not lead to symptomatic infarcts, there is also a lack of direct evidence that fibrous glassy lesions lead to symptomatic infarcts, so it is inappropriate to equate symptomatic infarcts due to penetrating artery lesions with small vessel disease, even if one does not consider that penetrating artery orifice atheromatous lesions are predominantly responsible for this type of disease, or at least to consider both penetrating artery orifice atheromatous lesions and fibrous glassy lesions. Fibrous vitreous lesions are two pathological changes that should be considered simultaneously. The concept of penetrating artery disease was introduced in the CISS to distinguish from the previous etiologic classification, which often equated penetrating artery lesions with small vessels, and to clearly introduce penetrating artery orifice atheromatous lesions into the etiologic diagnosis of this type. It would be ideal to distinguish between atheromatous lesions at the mouth of the penetrating artery and symptomatic infarct foci caused by fibrous glass in the clinical etiology, but although diffuse white matter sparing can respond to small arterial glassy lesions, it is still difficult to distinguish between the two in the clinical diagnosis because atherosclerosis and fibrous glassy lesions often coexist and current imaging cannot detect the condition of the wall of the penetrating artery. With the development of imaging, it will be possible to further classify penetrating artery disease in the future. In addition, the concept of penetrating artery disease has been introduced to avoid confusion not only with small vessel disease, but also with “luminal infarction”.
Description of the pathophysiologic mechanisms of stenosis
Although there are four types of pathogenesis, one of them is a mixed mechanism, so there are three main types, i.e., occlusion of a penetrating branch by a carrier artery (plaque or thrombus), artery-to-artery embolism, and decreased hypoperfusion/embolus clearance. For lesions of the internal carotid artery initiation and extracranial segment of the vertebral artery, thrombus formation on the surface of the plaque exacerbates the stenosis and may subsequently lead to complete occlusion.
Atherosclerotic thrombotic stenosis or occlusion of the carotid artery has several characteristics.
1, no infarct foci if plaque fragments or thrombosis are not dislodged and if Willis ring side branches are well compensated
2, if the plaque fragment or thrombosis is not dislodged but the Willis ring collateral branches are poorly compensated, which may lead to a watershed infarct in the presence of induced perfusion deficits such as decreased blood pressure, called hypoperfusion.
3, If plaque fragments or thrombus formation dislodges distally, it is called artery-to-artery embolism or embolus clearance decline depending on the site of infarction. The pathogenesis of infarction in vertebral artery lesions is similar to that of the extracranial segment of the internal carotid artery. In the case of large intracranial arteries, such as the middle cerebral artery, thrombus formation on the surface of the plaque can aggravate the stenosis and may subsequently lead to complete occlusion.
Atherosclerotic thrombotic stenosis or occlusion of the middle cerebral artery has the following characteristics.
1, if the plaque fragment or thrombus is not dislodged and does not block the penetrating artery, and the cortical soft meningeal collateral is well compensated, the new collateral vessels supplying the area of the penetrating artery are abundant, and the whole middle cerebral artery blood supply area experiences prolonged ischemic tolerance, so that even if complete occlusion occurs, no infarct foci can appear in its blood supply area.
2, if the plaque fragment or thrombus does not dislodge and does not block the penetrating artery, but the collateral compensation is not abundant enough, it may lead to infarction in the watershed area in the presence of factors that induce a decrease in perfusion, such as a decrease in blood pressure, called hypoperfusion.
3, if thrombosis occludes the mouth of the penetrating artery, it causes infarct foci in the area of the penetrating artery, called carrier artery occlusion of the penetrating branch.
4, If plaque fragments or thrombus dislodges distally, depending on the site of infarct it is called artery-to-artery embolization or embolus clearance descent.
The pathogenesis of infarction in basilar artery lesions is similar to that of the middle cerebral artery. The pathogenesis of infarct foci occurring in the watershed area is referred to as hypoperfusion/decreased embolic clearance. Hypoperfusion refers to the presence of a watershed infarct in the junctional area due to a simple decrease in perfusion, whereas decreased embolic clearance refers to the infarction in the watershed area caused by a buildup of microemboli that are not easily cleared when they enter the junctional area where perfusion is relatively low. It is difficult to distinguish between these two pathogenic mechanisms. Of course, if a patient with more than 70% stenosis of the internal carotid artery or middle cerebral artery has a watershed infarct ipsilateral to the stenosis and microembolic signals are detected by TCD microembolic monitoring, the diagnosis of a mechanism of decreased embolic clearance is more certain, but even if microembolic signals are not detected by TCD microembolic monitoring, the existence of the mechanism cannot be denied. In the present case, it may be more appropriate to conflate the two mechanisms. So is it necessary to have a perfusion check to determine hypoperfusion? If a perfusion examination is performed and there is evidence of reduced perfusion, the diagnosis of hypoperfusion is quite certain, but even if no perfusion examination is performed, the presence of hypoperfusion is considered likely as long as the infarct foci occur in the watershed area. The diagnosis of hypoperfusion/reduced embolic clearance was made whenever an infarct focus occurring in the watershed area had a stenosis of more than 70% in the supply artery, regardless of whether a perfusion examination was performed or whether there was evidence of decreased perfusion.
In summary
CISS has not only an etiologic diagnosis, but also a pathogenic diagnosis. The classification of aortic arch atherosclerosis to large artery atherosclerosis in the etiologic diagnosis makes it more consistent with true pathologic changes. The introduction of penetrating artery disease in the etiologic diagnosis formally introduced atheromatous lesions into the etiologic diagnosis of penetrating arteries. The pathogenesis of atherosclerotic infarction of large arteries was distinguished into carrier artery plaque or thrombus occlusion of the penetrating branch, artery-to-artery embolism or decreased hypoperfusion/embolus clearance, and mixed types that can be identified with modern imaging techniques. These improvements not only bring stroke staging more in line with clinical practice, but also improve the understanding of stroke pathophysiological mechanisms through staging.