Type of infarct
Diagnosis
Cerebral infarction
If a CT scan performed within 28 days of symptom onset shows an area of low attenuation, no relevant abnormality, or an area of irregular high attenuation within a larger area of low attenuation (i.e., an area of hemorrhagic infarction) or if a necropsy examination shows an area of cerebral infarction (pale or hemorrhagic) in a region compatible with the clinical signs and symptoms
Lacunar infarct (LACI)
One of the four classic clinical lacunar syndromes. Patients with faciobrachial or brachiocrural deficits are included, but more restricted deficits are not
Total anterior circulation infarct (TACI)
Combination of new higher cerebral dysfunction (e.g., dysphasia, dyscalculia, visuospatial disorders), homonymous visual field defect, and ipsilateral motor and/or sensory deficit of at least two areas of the face, arm, and leg. If the conscious level is impaired and formal testing of higher cerebral function or the visual fields is not possible, a deficit is assumed
Partial anterior circulation infarct (PACI)
Only two of the three components of the TACI syndrome, with higher dysfunction alone, or with a motor/sensory deficit more restricted than those classified as LACI (e.g., confined to one limb, or to the face and hand but not the whole arm)
Posterior circulation infarcts (POCIs)
Any of the following: ipsilateral cranial nerve palsy with contralateral motor and/or sensory deficit, bilateral motor and/or sensory deficit, disorder of conjugate eye movement, cerebellar dysfunction without ipsilateral long-tract deficit (i.e., ataxic hemiparesis), or isolated homonymous visual field defect
11.1.2 Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Classification System
The earliest stroke classification system was the Stroke Data Bank Subtype Classification system [4]. It was composed of five classes developed when the National Institute of Neurological Disorders and Stroke (NINDS) established the Stroke Data Bank for the first time. These classes were brain hemorrhage, brain infarction (atherothrombotic and tandem arterial pathological abnormalities), cardioembolic stroke, lacunar stroke, and stroke from rare causes or with an undetermined etiology. Since 1993, almost all the clinical researchers in the world have been using the classification system suggested by the TOAST clinical researchers [2]. This classification method was originally intended to be used for comparing and analyzing the effect of danaparoid among the different subtypes of stroke. The basic principle of classification in this method was not significantly different from that of the Stroke Data Bank Subtype Classification system. The TOAST researchers originally divided stroke cases into eleven groups and then narrowed these down to five (Table 11.2). This classification method has the highest internal validity when the planned algorithms are followed strictly. Possible errors in classification are mostly corrected by discussion and agreement between specialized researchers. In the case of the lacunar stroke, however, which is defined by the clinical conditions and size of the stroke, there is still a risk of misclassification, where large-artery atherosclerosis (LAA) is mistaken as small-vessel occlusion (SVO) if there is an atherosclerotic artery that is too tiny to be spotted and clearly seen on MRI. As the definition of LAA includes 50% or more stenosis in the relevant arteries, it is still possible that a patient who is certain to have LAA can be classified with an undetermined etiology. It is also true that depending on the level of experience of the physician, the stroke cause may still be undetermined even if one of the candidate causes looks more promising. In this classification method, the ratio of undetermined causes is overestimated. Furthermore, while the cardioembolic stroke causes are classified into high- and medium-risk factors, patent foramen ovale (PFO), which has a high prevalence rate among normal individuals, is also a medium-risk factor. PFO may not be counted as cardioembolic causes and may be included in some cases. Accordingly, many researchers modify the TOAST classification system to suit their purposes. As there is no single modified version of this classification that is widely supported, however, it would suffice for the readers to understand the concept of the TOAST system clearly.
Table 11.2
TOAST classification
Type of infarct | Diagnosis |
|---|---|
Large-artery atherosclerosis | Clinical evidence of cortical, subcortical, brain stem, or cerebellar dysfunction with more than 50% lesion or occlusion in an extracranial or intracranial vessel in the distribution of an infarct larger than 1.5 cm by CT or MRI. This diagnosis cannot be made if arterial studies show no evidence of pathology or if there is reasonable suggestion by history or studies that another mechanism is possible |
Cardioembolism (high risk/medium risk) | Clinical evidence of cortical, subcortical, brain stem, or cerebellar dysfunction with a lesion size larger than 1.5 cm on CT or MRI and the presence of at least one high-risk (e.g., atrial fibrillation or mechanical heart valve) or medium-risk (e.g., lone atrial fibrillation or patent foramen ovale) cardiac pathology on diagnostic studies (electrocardiogram, rhythm strip, 24-h cardiac monitoring, transthoracic, or transesophageal echocardiography). Evidence of transient ischemic attacks or strokes in more than one vascular territory or of systemic emboli supports the diagnosis. Finally, other categories (large artery, small artery) must be excluded |
Small-vessel occlusion (lacunar) | A lacunar syndrome (pure motor, sensorimotor, pure sensory, ataxia hemiparesis, dysarthria-clumsy hand) with normal CT or MRI or a lesion smaller than 1.5 cm on CT or MRI in the territories supplied by small-vessel penetrators. Large-artery and cardiac sources must be excluded |
Stroke of other determined etiology | Stroke caused by nonatherosclerotic vasculopathies, hypercoaguable states, or hematologic disorders and other rare causes of stroke after diagnostic testing. Other categories must be excluded |
Stroke of undetermined etiology (cryptogenic) | This diagnosis is made if two or more etiologies of stroke are possible, a complete evaluation reveals no possible source, or the patient had an incomplete evaluation |
11.2 Stroke Cases Classified Using the TOAST Classification System
To understand the classification and behavior of stroke, thrombosis, the main reason for the occlusion of the blood vessels, must first be understood. Thrombosis is the final product of the blood coagulation process and mainly consists of two parts: the platelet plugs and the fibrin meshwork. Normally, the conditions leading to the generation of thrombosis are collectively known as “Virchow’s triad,” which are (1) damages to the endothelial cells, trauma or arthrosclerosis; (2) abnormal blood flow, loss of laminar flow due to the delay of the flow in the veins or the turbulences in the arteries; and (3) hypercoagulability [5]. The thrombi can be classified into white thrombi, mostly composed of platelet plugs; red thrombi, mainly composed of red blood cells; and mixed thrombi, mixtures of the two. In stroke, all the three types of thrombi occur and are based on the type of thrombus that contributed most to the condition; the initial progress, the effectiveness of the treatment during the acute phase, and the treatment approaches for prognosis and secondary prevention are likely to be different. It is critical to identify the mechanism of thrombosis as well as relevant risk factors for the proper diagnosis and treatment of a stroke patient.
11.2.1 LAA
First, let me introduce the concept of the term large artery. This term is not basically used in the traditional anatomy, and it is not appropriate to understand it to be different from the small vessels based on the vascular histology. There are no clear definitions on the terms, but I suggest the following working definition: a blood vessel stemming from the vessels traveling toward the brain (aorta, brachiocephalic trunk, and common carotid artery) to those running the subarachnoid space in the brain. For more information, kindly refer to “Pathophysiology of Stroke,” to be published as one of the Stroke Revisited series by the publisher, Springer Nature Inc.
The most important etiology of stroke among the vascular diseases in large arteries is atherosclerosis. Atherosclerosis is a chronic inflammatory disease mainly caused by the lipid on the walls of the artery due to innate and adaptive immunity. At first, it accompanies a functional disorder of the endothelial cells while the wall is exposed to an excessive amount of low-density lipoprotein (LDL), causing the LDL to pile up inside the intima (Fig. 11.1). With continued exposure to vascular risk factors (e.g., hypertension, diabetes, smoking, infection, stress, etc.), the damages to the endothelial cells are aggravated, and these damaged cells cause more LDL particles to be accumulated on the extracellular matrix. As a result, this area suffers the most from free radicals and cytokines. The modified LDL activates various inflammatory reactions. The main mechanism is the infiltration of the monocyte cells, which plays the most profound role in innate immunity. Monocytes come inside and reach the subendothelial areas to be differentiated into macrophages by the macrophage colony-stimulating factors. Macrophages accept the modified LDLs easily and develop pattern recognition receptors on the surface. Then it becomes lipid-containing macrophages and finally foam cells. The accumulation of foam cells leads to a disease in the arterial system through the movement of the vascular smooth muscle cells and the formation of a fibrous cap. Vascular status like this is called is “atherosclerotic plaques.” The atherosclerotic plaques proceed to develop into thrombosis, which is the cause of LAA-related stroke.
Fig. 11.1
Progression of atherosclerotic lesion (shown as time sequence from left to right)
Stable atherosclerotic plaques rarely result in stroke. Unstable or vulnerable plaques are the cause of LAA-related stroke. Most of these observations have originated from the coronary artery study reports. The World Health Organization (WHO) classified atherosclerotic plaques for the first time in 1958 [6]. Four classes were identified: fatty streak, atheroma, fibrous plaque, and complicated lesion. In the mid-1990s, the American Heart Association (AHA) recommendeds new classification criteria for atherosclerotic plaque (Table 11.3; Fig. 11.2) [7, 8]. This classification was followed by recommendations from several researchers who found out that plaque erosion could result in coronary thrombosis, which further refined the classification system. Currently, the pathological classification of coronary artery atherosclerosis is based on this system, and the classification of atherosclerotic plaque on the cerebral artery is yet to be suggested. With minor differences in vascular histology among the organs, cerebral atherosclerotic process is not likely to be different from coronary atherosclerosis. Therefore, it is appropriate to understand ischemic stroke due to LAA from the classification system of coronary atherosclerosis. As the classification states, atherosclerotic plaques, which result in thrombosis, consist in plaque rupture, plaque erosion, and calcified nodules. Such lesions stimulate and activate platelets, and this marks the beginning of thrombosis. Later, due to the activated platelets, the platelets adhere to the atherosclerotic lesion and aggregate to form primary plugs. Due to the activation of clotting factors, the primary plugs condensate by fibrin meshwork, which completes the process of generating thrombosis. In this way, the thrombi that originate from a stroke caused by LAA are mainly white thrombi, while the thrombi generated from CE are basically red thrombi. Atherosclerotic plaque, which functions as the cause of thrombosis, is mostly attributable to plaque rupture, followed by plaque erosion and calcified nodule. These are the incidences in the coronary events, and it is yet to be confirmed if the incidences will be reproduce in the LAA-related stroke.
Table 11.3
Classification of atherosclerotic lesion
Type of lesion | Subtype of lesion | Morphological description |
|---|---|---|
Nonatherosclerotic intimal lesions | Intimal thickening | Natural accumulation of smooth muscle cells in the absence of lipid, macrophage foam cells, and thrombosis |
Intimal xanthoma | Superficial accumulation of foam cells without a necrotic core, fibrous cap, or thrombosis | |
Progressive atherosclerotic lesions | Pathological intimal thickening | Plaque rich in smooth muscle cells, with hyaluronan and proteoglycan matrix and focal accumulation of extracellular lipid. Absence of thrombosis |
Fibroatheroma | During early necrosis: focal macrophage infiltration into areas of lipid pools with an overlying fibrous cap. During late necrosis: loss of matrix and extensive cellular debris with an overlying fibrous cap. With or without calcification. Absence of thrombosis | |
Intraplaque hemorrhage or plaque fissure | Large necrotic core (size >10% of plaque area) with hemorrhage and plaque area shows the presence of angiogenesis. Necrotic core communicates with the lumen through a fissure. Minimal tear without obvious thrombus | |
Thin-cap fibroatheroma | A thin, fibrous cap (<65 μm) infiltrated by macrophages and lymphocytes, with rare or no smooth muscle cells and relatively large underlying necrotic core (>10% of plaque area). Intraplaque hemorrhage and/or fibrin might be present. Absence of thrombosis
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