INTRODUCTION — Stroke and transient ischemic attack (TIA) are caused by one of several pathophysiologic processes involving the blood flow of the brain:
●The process may be intrinsic to the vessel, as in atherosclerosis, lipohyalinosis, inflammation, amyloid deposition, arterial dissection, developmental malformation, aneurysmal dilation, or venous thrombosis.
●The process may originate remotely, as occurs when an embolus from the heart or extracranial circulation lodges in an intracranial vessel.
●The process may result from inadequate cerebral blood flow due to decreased perfusion pressure or increased blood viscosity.
●The process may result from rupture of a vessel in the subarachnoid space or intracerebral tissue.
The first three processes can lead to transient cerebral ischemia (transient cerebral ischemic attack or TIA) or permanent cerebral infarction (ischemic stroke), while the fourth results in either subarachnoid hemorrhage or an intracerebral hemorrhage (primary hemorrhagic stroke).
This topic will discuss the definition, etiology, and clinical manifestations of TIA. The clinical diagnosis, evaluation, and treatment of TIA are discussed separately. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke" and "Differential diagnosis of transient ischemic attack and acute stroke" and "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".)
DEFINITION OF TIA
Traditional time-based definition of TIA — TIA was originally defined as a sudden onset of a focal neurologic symptom and/or sign lasting less than 24 hours, brought on by a transient decrease in blood flow, which renders the brain ischemic in the area producing the symptom. The time limit was intended to separate ischemia without infarction from infarction. However, this classic, time-based definition of TIA is inadequate for several reasons. Most notably, there is risk of permanent tissue injury (ie, infarction) even when focal transient neurologic symptoms last less than one hour.
Tissue-based definition of TIA — In the tissue-based definition, TIA is a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction . In keeping with this definition of TIA, ischemic stroke is defined as an infarction of central nervous system tissue (brain, spinal cord, or retinal cells) attributable to ischemia, based on neuropathologic, neuroimaging, and/or clinical evidence (ie, persistence of symptoms or findings) of permanent tissue injury .
Thus, the benign connotation of "TIA" has been replaced by an understanding that even relatively brief ischemia can cause permanent neurologic or retinal injury. (See 'Symptom duration and infarction' below.)
The advantages of tissue-based definitions of TIA and stroke include the following [1,3]:
●The end point is biologic (tissue injury, as confirmed or excluded by neuroimaging) rather than arbitrary (24 hours)
●The definition encourages use of neurodiagnostic tests to identify brain injury and its cause, which furthers earlier therapeutic interventions
●The presence or absence of ischemic brain is more accurately reflected
The shortcomings of tissue-based definitions of TIA/stroke include the following:
●Dependency on the sensitivity and availability of neuroimaging – Infarctions associated with classically-defined TIA are often very small; most are less than 1 mL in volume . Imaging methods that have low sensitivity for small infarcts, such as computed tomography (CT) or conventional magnetic resonance imaging (MRI), would result in some transient events being inappropriately classified as TIA without acute infarction. Conversely, imaging with diffusion-weighted MRI (DWI), with its higher sensitivity for acute infarction, would increase the proportion of transient events classified as ischemic stroke . High variance in practice for imaging in patients with suspected TIA would reduce the ability to compare studies from different institutions as well as from different time periods.
●Dependency on population and case-mix – The diagnosis of TIA without acute infarction depends not only on the sensitivity of imaging but also on clinical judgment as to whether the signs and symptoms are consistent with an ischemic syndrome and therefore warrant an imaging study. Hence, the prevalence of TIA without acute infarction depends on the population characteristics and the case mix, particularly the mixture of typical and atypical transient spells (see 'Typical TIA' below and 'Atypical TIA' below). There is a high variance in the prevalence of brain infarcts for TIA defined by time (ie, transient symptoms lasting <24 hours), with infarct rates ranging from 4 to 34 percent by CT and 21 to 67 percent by diffusion-weighted MRI .
Symptom duration and infarction — The duration of ischemic symptoms does not reliably distinguish whether a symptomatic ischemic event will result in ischemic infarction . A classically defined TIA with symptoms lasting for as little as a few minutes can be associated with infarction on DWI, whereas a spell lasting for many hours may show no signs of infarction on DWI. In patients with prolonged symptoms without development of infarction, concern for a nonischemic etiology of the spell should be raised .
Some reports suggest that increased duration of classically defined TIA (<24 hours in duration) is associated with a higher probability of infarction on DWI, but the association is not absolute [4,8-11]. A systematic analysis of patients with classically defined TIA found that symptom duration was not a reliable predictor for the presence of infarction (figure 1), even though the mean duration tended to be significantly longer in patients with infarction than in those without infarction .
One potential caveat is that abnormalities on initial imaging, such as DWI obtained during or soon after symptoms, may actually be reversible injuries. However, most patients with TIA seek medical attention after their symptoms fully resolve; a low proportion (≤7 percent) of patients with classically defined TIA are admitted and scanned at the height of their symptoms [8-10,12]. Therefore, infarcts observed in patients with classically defined TIA most likely represent permanent brain injury, as the probability of DWI reversibility decreases as the time from symptom onset to imaging increases.
EPIDEMIOLOGY — TIA is a common neurologic problem . In a population-based cohort study from 1948 to 2017 of over 14,000 predominantly White participants from the Framingham Heart Study, the estimated overall incidence of TIA was 1.19 per 1000 person-years . The incidence increased with age; for the age group 45 to 54 years, the incidence was 0.22 per 1000 person-years, while for the age group 85 to 94 years, the incidence was 4.88 per 1000 person-years.
In a community-based registry study from Italy, the annual incidence of TIA from 2007 to 2009 was 0.52 per 1000 population . In the Cincinnati and Northern Kentucky region of the United States, where the ethnic and socioeconomic demographics are similar to that of the United States as a whole, another population-based study found that the adjusted annual incidence rate for TIA from 1993 to 1994 was 0.83 per 1000 population, and that Black individuals and men had significantly higher rates of TIA than White individuals and women . From these data, it was estimated that 240,000 TIAs occurred in the United States in 2002.
The estimated overall prevalence of TIA among adults in the United States is approximately 2 percent . This number is felt to under-represent the true prevalence of TIA. Poor awareness by lay-persons of the signs and symptoms of cerebral or ocular ischemia and the risk of subsequent stroke, combined with a high rate of failure to seek medical attention after a TIA, may account for this finding .
Use of the tissue-based definition of TIA in epidemiologic studies is likely to modestly alter the incidence and prevalence rates of TIA and stroke, but these changes are encouraged because they should reflect more accurate diagnosis . Data from several reports suggest that defining TIA by the absence of infarction on imaging will decrease the annual rate of TIA by approximately 30 percent and increase the annual incidence of stroke by 7 percent [19-21].
MECHANISMS AND CLINICAL MANIFESTATIONS — A TIA should be considered a syndrome. The symptoms of a TIA depend in part upon the pathophysiologic subtype, which are divided into three main mechanisms:
●Embolic TIA, which may be artery-to-artery, or due to a cardioaortic or unknown source
●Lacunar or small penetrating vessel TIA
●Large artery, low-flow TIA
Embolic TIA — Embolic TIAs are characterized by discrete, usually single (and not stereotyped if multiple), more prolonged episodes of focal neurologic symptoms. The embolus may arise from a pathologic process in an artery, usually extracranial, or from the heart (eg, atrial fibrillation or left ventricular thrombus) or aorta. A diligent search for a potential embolic source is necessary in all cases of TIA. (See "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".)
Embolic TIAs may last hours rather than minutes as in low-flow TIAs. As an example, in one study that divided patients with TIAs into those with symptoms of short duration (less than 60 minutes) or long duration (60 minutes or greater), the latter group was more likely to have an embolic source (86 versus 46 percent) . Embolic TIAs also may less likely be repetitive compared with low-flow TIAs since they are the result of emboli from a specific source (eg, a one-, two-, or three-time phenomenon). When the source of the embolus is in a proximal vessel, recurrent emboli can lodge in different branches of the parent vessel giving different symptoms.
Emboli are subject to natural thrombolysis and migration since they typically break off of fresh thrombus. They may produce transient ischemia on many occasions, but an element of silent infarction remains.
Embolic TIAs are best divided into those in the anterior cerebral circulation (carotid, anterior cerebral artery, middle cerebral artery territory) and those in the posterior cerebral circulation (vertebrobasilar, posterior cerebral artery territory). Symptoms in both circulations depend upon the size of the embolic fragment in relation to the size of the artery occluded.
●Anterior circulation embolic TIAs – Embolic TIAs in the anterior circulation may be large enough to occlude the middle cerebral artery stem, producing a contralateral hemiplegia secondary to ischemia in the deep white matter and basal ganglion/internal capsule lenticulostriate territory (figure 2). In addition, they may produce cortical surface symptoms. These include aphasic and dysexecutive syndromes in the dominant hemisphere and anosognosia or neglect in the nondominant hemisphere.
Smaller emboli that occlude branches of the middle cerebral artery stem result in more focal symptoms, including hand alone or arm and hand numbness, weakness, and/or heaviness induced by ischemia to the frontal area of the contralateral frontal lobe motor system (figure 3). Rarely, the symptoms also may be as specific as thumb or hand numbness or a swollen feeling, suggesting focal ischemia in the hand area of the sensory strip or parietal association cortex. Isolated upper limb weakness may implicate cervical carotid atherosclerosis as the cause of cerebral ischemic symptoms .
Transient monocular visual loss often signifies atherothrombotic disease in the internal carotid artery proximal to the ophthalmic artery origin (see "Amaurosis fugax (transient monocular or binocular visual loss)"). Atherothrombotic disease is most often responsible for these syndromes, although carotid dissection and embolism from the aorta, heart, or an unknown source also should be considered. In a report of 129 patients with monocular visual loss of presumed ischemic origin, diffusion-weighted MRI of the brain revealed concurrent acute brain infarcts in 24 percent . These infarcts were typically small, often multiple, frequently ipsilateral to the involved eye, and usually asymptomatic. The finding of concurrent acute brain infarction in a patient with transient monocular visual loss suggests a proximal source of embolic particles that travel to both the retinal and hemispheric circulations.
●Posterior circulation embolic TIAs – Posterior circulation territory embolic TIAs are generally produced by emboli arising from atherothrombotic disease at the origin or distal segment of one of the vertebral arteries or of the proximal basilar artery. Emboli arising from the aortic arch, the heart, an unknown source, or from a dissecting lesion in the vertebral artery should also be considered.
Symptoms vary according to the vertebral or basilar artery branch in which the embolus lodges (figure 4). Emboli can produce transient ataxia, dizziness, diplopia, dysarthria, quadrantanopsia, hemianopsia, numbness, crossed face and body numbness, and unilateral hearing loss. When the top of the basilar artery is embolized, sudden, overwhelming stupor or coma may ensue due to bilateral medial thalamic, subthalamus, and medial rostral midbrain reticular activating system ischemia. Emboli in the more distal branches of the posterior cerebral artery may result in a homonymous field defect or in memory loss (inferior medial temporal lobe ischemia).
Lacunar or small vessel TIA — Lacunar or penetrating or small vessel TIAs are due to transient cerebral ischemia induced by stenosis of one of the intracerebral penetrating vessels arising from the middle cerebral artery stem, the basilar artery, the vertebral artery (figure 5), or the circle of Willis (figure 6 and figure 7). Occasionally, recurrent stereotyped TIAs occur; in this setting, the term lacunar or small vessel TIAs seems appropriate.
Most often, lacunar or small vessel TIAs are thought to be caused either by atherothrombotic obstructive lesions at the origin of the penetrating vessel or by lipohyalinosis distally within the penetrating vessel. Less commonly, embolism may cause lacunar or small vessel TIAs. (See "Lacunar infarcts", section on 'Etiology'.)
These small vessel TIAs cause symptoms similar to the lacunar strokes that are likely to follow. Thus, face, arm, and leg weakness or numbness due to ischemia in the internal capsule, pons, or thalamus may occur, similar to the symptoms due to ischemia from embolism or large vessel atherothrombotic disease or dissection. As a result, serious disease in the parent vessel must be excluded before the diagnosis of lacunar or small vessel TIA can be established with confidence.
Lacunar infarcts may be preceded by lacunar TIAs consisting of brief repetitive stereotyped clinical symptoms and signs, and lacunar stroke onset may be stepwise and progressive rather than abrupt [25-27]. Such a pattern of TIAs, or non-sudden onset in association with a lacunar syndrome, is highly suggestive of small vessel lipohyalinotic etiology . (See "Lacunar infarcts".)
Low-flow TIA — Large artery low-flow TIAs are often associated with a tightly stenotic atherosclerotic lesion at the internal carotid artery origin or in the intracranial portion of the internal carotid artery (siphon) when collateral flow from the circle of Willis to the ipsilateral middle or anterior cerebral artery is impaired (figure 6 and figure 7). Other important causes include atherosclerotic stenotic lesions in the middle cerebral artery stem (figure 3) or at the junction of the vertebral and basilar artery. Any obstructive vascular process in the extracranial or intracranial arteries can cause a low-flow TIA syndrome if collateral flow to the potentially ischemic brain also is diminished.
Low-flow TIAs usually are brief (minutes) and often recurrent. They may occur as little as several times per year but typically occur more often (once per week or up to several times per day).
●Anterior circulation low-flow TIAs – Low-flow TIAs are generally stereotyped, especially when they are due to hemodynamically significant stenotic lesions at the origin of the internal carotid artery, at the siphon portion of the internal carotid artery where collateral flow to the circle of Willis is inadequate, or in the middle cerebral artery stem. Symptoms due to ischemia from these lesions often include weakness or numbness of the hand, arm, leg, face, tongue, and/or cheek. Recurrent aphasic syndromes appear when there is focal ischemia in the dominant hemisphere, and recurrent neglect occurs in the presence of focal ischemia in the nondominant hemisphere ischemia. Limb-shaking TIAs are a rare, but classic, hypoperfusion syndrome of repetitive jerking movements of the arm or leg due to a severe stenosis or occlusion of the contralateral internal carotid or middle cerebral artery [29-31].
●Posterior circulation low-flow TIAs – In contrast, recurrent symptoms are often not stereotyped when the stenotic lesion that obstructs flow involves the vertebrobasilar junction or the basilar artery. The many closely packed neuronal structures in the brainstem preclude consistent manifestations of recurrent focal ischemia in this area.
Nevertheless, certain generalizations about recurrent low-flow TIA symptoms in the posterior circulation can be made.
•Obstructive lesions in the distal vertebral artery or at the vertebrobasilar junction usually cause dizziness that may or may not include spinning or vertigo. The patient may complain that the room is tilting or that the floor is coming up at them, rather than spinning dizziness. Patients may use the word dizziness to describe a myriad of symptoms, not necessarily spinning. Other symptoms can include numbness of one side of the body or face, dysarthria, or diplopia.
•Ischemia in the pons from stenotic lesions in the proximal to mid-basilar artery can cause bilateral leg and arm weakness or numbness and a feeling of heaviness in addition to dizziness.
•Ischemia in the territory of the top of the basilar artery or proximal posterior cerebral artery may present with all of the above recurrent symptoms as well as overwhelming drowsiness, vertical diplopia, eyelid drooping, and an inability to look up. Transient ischemia at the top of the basilar artery is usually due to embolism rather than low-flow TIA.
URGENCY OF EVALUATION — TIA is a neurologic emergency (table 1). Patients with TIA and minor, nondisabling stroke have a high early risk of recurrent stroke (see 'Risk of recurrent stroke' below). Recognition of TIAs can identify patients who may benefit from preventive therapy. Therefore, the initial management of suspected TIA and minor ischemic stroke includes immediate antiplatelet treatment and urgent evaluation (algorithm 1). This is reviewed in detail separately. (See "Initial evaluation and management of transient ischemic attack and minor ischemic stroke".)
DIAGNOSIS — The diagnosis of TIA is based upon the clinical features of the transient attack and the neuroimaging findings . Since few patients with suspected TIA present when fully symptomatic , determining the likelihood of ischemia as the cause of the event often depends upon the history as reported by the patient and witnesses.
Typical TIA — Typical TIAs are characterized by transient, focal neurologic symptoms, generally with sudden onset, that can be localized to a single vascular territory within the brain, including one or more of the following:
●Transient monocular blindness (amaurosis fugax)
●Aphasia or dysarthria
●Hemiparesis and/or hemisensory loss
In such cases, the likelihood of ischemia is relatively high. However, events consistent with typical TIA may sometimes occur due to nonischemic mechanisms such as seizure, migraine, intracerebral hemorrhage, and others. (See "Differential diagnosis of transient ischemic attack and acute stroke".)
A key problem with the diagnosis of TIA is how to determine if symptoms are caused by ischemia when brain imaging is normal. Although clinical features are not definitive for etiology, an ischemic insult is the most likely cause when the attack is consistent with a typical TIA (ie, one with transient, focal neurologic symptoms localizing to a single vascular territory).
Atypical TIA — The clinical characteristics of transient symptoms considered to be atypical of an ischemic attack include the following [33-35]:
●Gradual build-up of symptoms (more than five minutes)
●March of symptoms from one body part to another (without passing the midline)
●Progression of symptoms from one type to another
●Isolated disturbance of vision in both eyes characterized by the occurrence of positive phenomena (eg, flashing lights)
●Isolated sensory symptoms with remarkably focal distribution, such as in a finger, chin, or tongue
●Very brief spells (less than 30 seconds)
●Identical spells occurring over a period of more than one year
●Isolated brainstem symptoms, such as dysarthria, diplopia, or hearing loss
●Incoordination of limbs
With atypical attacks as defined above, the likelihood of an ischemic cause may be relatively low. In several reports, the proportion of patients with atypical attacks who had acute brain infarction on diffusion weighted magnetic resonance imaging (MRI) was approximately 10 percent, suggesting that a minority of atypical spells have an ischemic cause and are therefore TIAs [6,36,37]. Alternatively, it may be the case that the sensitivity of MRI is not sufficient to reveal the ischemic lesions associated with atypical spells. One report that evaluated 275 patients with definite vertebrobasilar territory infarction found that preceding transient isolated brainstem symptoms occurred in 16 percent, suggesting that isolated brainstem symptoms can sometimes signify an ischemic attack .
However, there is evidence that patients with atypical TIAs characterized by negative focal symptoms (where "negative" indicates a loss of some neurologic function) have similar short- and long-term risks of subsequent ischemic stroke as do patients with typical TIAs and should therefore be investigated and treated as true TIAs. A population-based longitudinal cohort study from the United Kingdom prospectively evaluated patients with minor ischemic stroke (n = 1287), classic TIA (n = 1021), or nonconsensus TIA (n = 570), the latter defined by isolated vertigo, isolated ataxia, isolated diplopia, isolated speech disturbance (slurred speech) without aphasia, isolated bilateral decreased vision, or isolated unilateral sensory loss involving only one body part (face, arm, hand, or leg) . All patients were treated according to secondary prevention guidelines; the median follow-up was 5.2 years. At baseline, the prevalence of stroke risk factors including atrial fibrillation, arterial stenoses, and patent foramen ovale was similar for nonconsensus and classic TIA. Furthermore, the 90-day stroke risk after the index event was similar for nonconsensus TIA (10.6 percent [95% CI 7.8-12.9]) and classic TIA (11.6 percent [95% CI 9.6-13.6]), as was the 10-year risk of major vascular events (27.1 versus 30.9 percent).
Differential diagnosis — The differential diagnosis of TIA (table 1) is discussed in detail separately. (See "Differential diagnosis of transient ischemic attack and acute stroke".)
RISK OF RECURRENT STROKE — TIA is a neurologic emergency because patients with time-based TIA and minor, nondisabling stroke are at increased risk of recurrent stroke, especially in the days following the event.
Factors that affect stroke risk — The risk of stroke after TIA appears to vary according to several factors, including time after the index event, presence of vascular pathologies, and the presence of acute infarction on MRI scan.
●The first days after the event – The risk of stroke is highest in the first days after a TIA, ranging from 1.5 to 3.5 percent in the first 48 hours after TIA, making up approximately 40 percent of the 90-day stroke risk [39-42]. The urgency associated with TIA derives also from the observation that TIAs are most likely to occur in the hours and days immediately preceding ischemic stroke. As an example, a study that analyzed four cohorts of patients who had recent ischemic stroke found that TIAs occurred most often in the 48 hours prior to the stroke . Another study found that the risk of ischemic stroke occurring within 24 hours of a probable or definite TIA was approximately 5 percent . Of all ischemic strokes during the 30 days after a first TIA, 42 percent occurred within the first 24 hours. This may be an overestimate related to the difficulty distinguishing a single ischemic event (stroke) with fluctuating symptoms from separate events (TIA followed by stroke) within a short period of time. Nevertheless, these observations underscore the high early risk of developing a permanent deficit after transient ischemic symptoms and the importance of urgent assessment, risk stratification, and treatment.
Given this short time window and high risk of stroke (1.5 to 3.5 percent in the first 48 hours after TIA [39,40]) neurologic evaluation of and intervention for TIA should occur urgently. Recognition and urgent evaluation of TIAs can identify patients who may benefit from preventive therapy or from revascularization of large vessels such as the carotid artery. Premonitory carotid territory TIAs occur in approximately 50 to 75 percent of patients with ischemic stroke from extracranial carotid disease [44-46], and vertebrobasilar TIAs are associated with a risk of subsequent stroke or death that is similar to or possibly higher than that seen with carotid TIAs .
●Higher risk with vascular pathologies – TIA caused by vascular pathologies (ie, large artery atherosclerosis and small vessel disease) appears to confer a higher risk of subsequent stroke than cardiac and other nonvascular subtypes of TIA. A study from the prospective TIAregistry.org project, with over 4700 patients, found that large artery atherosclerosis was an independent risk factor for recurrent stroke .
Another prospective population-based study of 1000 patients from the United Kingdom reported that TIA due to small vessel vasculopathy was associated with a higher risk of early stroke than TIA due to other causes . The stroke risk was particularly elevated after multiple stereotyped small vessel TIAs occurring in a brief period of time and characterized by motor symptoms but no cortical signs, the so-called "capsular warning syndrome"  or "stuttering lacunar syndrome." Although data are limited, the risk of early (within seven days) stroke after such events may be as high as 40 percent or more [27,48].
●Higher risk with infarction – There is accumulating evidence suggesting that the findings of acute infarction on diffusion-weighted MRI (DWI) [32,49-52] or acute or chronic ischemic lesions on computed tomography (CT)  after a transient ischemic event are important predictors of stroke. As an example, in a pooled analysis of 3206 patients with TIA who were evaluated with DWI, the risk of stroke at seven days was much lower in patients with no infarction compared with those with infarction (0.4 versus 7.1 percent) . In patients with an imaging-positive transient event, the 90-day risk of stroke appears to be as high as 14 percent [32,49,50,54]. In contrast, after an imaging-negative transient event, the corresponding risk is <1 percent.
●Is the stroke risk after TIA declining over time? – In a 2016 report from the TIAregistry.org project, a prospective multinational registry of over 4700 patients with TIA or minor stroke (defined by a modified Rankin scale score of 0 or 1 when first evaluated), the estimated risks of stroke at 2, 30, 90, and 365 days after the index event were 1.5, 2.8, 3.7, and 5.1 percent, respectively . In a 2018 follow-up study, the estimated cumulative risk of stroke at five years after the index event was 9.5 percent . These rates are lower than those previously reported [40,56,57], possibly due to the more rapid implementation of newer and more effective strategies for the secondary prevention of ischemic stroke; the registry included only sites with dedicated systems for the urgent evaluation of TIA, and most patients were seen by a stroke specialist within 24 hours of symptom onset. Independent risk factors for recurrent stroke were multiple infarctions on brain imaging, large artery atherosclerosis, and an ABCD2 score of 6 or 7. (See 'Stroke risk stratification' below.)
A systematic review and meta-analysis of 68 studies published from 1971 to March 2019 that included over 200,000 patients found that the risk of stroke after TIA was 2.4 percent within two days, 3.8 percent within seven days, 4.1 percent within 30 days, and 4.7 percent within 90 days . The incidence of stroke was lower among study populations enrolled after 1999. Similarly, in a longitudinal population-based cohort study from the Framingham Heart Study that included over 14,000 participants from 1948 to 2017 with no history of TIA or stroke at baseline, the risk of stroke after TIA was lower in the epoch of 2000 to 2017 compared with 1948 to 1985 .
High-risk lesions — There are four pathologic processes that give rise to embolic TIAs or low-flow TIAs and that can produce sudden devastating stroke if not recognized and treated.
●Internal carotid artery atherosclerosis – An atherothrombotic stenotic lesion at the origin of the internal carotid artery that is narrowed to more than 70 percent of its normal lumen diameter poses a threat of embolic or low-flow TIA or stroke [58-61]. Even a 50 percent stenosis may be important when considering carotid endarterectomy for prevention of a secondary stroke or of a primary stroke when a TIA has occurred. In this setting, embolism is more common than low flow as a cause of TIA or stroke. (See "Management of symptomatic carotid atherosclerotic disease".)
Prospective natural history studies of asymptomatic atherothrombotic disease at the origin of the internal carotid artery (mostly asymptomatic carotid artery bruits) suggest that the rate of ipsilateral stroke increases dramatically when the residual lumen diameter narrows to greater than 70 percent stenosis (figure 8 and figure 9) [62-64]. In one series of 500 patients with asymptomatic cervical bruits, the incidence of stroke was 1.7 percent per year overall but 5.5 percent per year in those with more than a 75 percent carotid artery stenosis .
This degree of stenosis corresponds to a residual lumen diameter of 1.5 mm, the precise point at which pressure drops across the stenotic lesion [65,66]. When the pressure drops, flow to the ipsilateral middle cerebral artery stem is in part supplied by collateral circulation from the circle of Willis and from the external carotid to ophthalmic to distal internal carotid artery system (figure 6 and figure 7). Less flow is provided by the internal carotid artery as the lesion further narrows. We believe that this provides a milieu for thrombus formation at the site of the stenosis and subsequent embolism. When the circle of Willis is compromised, low-flow TIA ensues.
●Intracranial atherothrombotic disease — Intracranial atherothrombotic disease that produces low-flow or embolic TIA most commonly occurs at the distal vertebral artery/vertebrobasilar junction/proximal basilar artery site. The potential of this lesion to precipitate a disastrous stroke by thrombosis, thrombus propagation, and embolism is extremely important. The other two most important, but less common, sites include the siphon portion of the internal carotid artery and the middle cerebral artery stem. The common carotid artery origin and the vertebral artery origin are much less problematic since they only rarely give rise to artery-to-artery emboli.
The ability to noninvasively diagnose and follow these intracranial arterial lesions with precision through MRI angiography, CT angiography, duplex Doppler, and transcranial Doppler flow assessment allows for important preventive therapeutic considerations. (See "Intracranial large artery atherosclerosis: Treatment and prognosis" and "Overview of secondary prevention for specific causes of ischemic stroke and transient ischemic attack".)
●Arterial, aortic, or cardiac sources of emboli — Emboli at the top of the basilar artery or the middle cerebral artery stem that come from a source below — arterial, aortic, or cardiac — are extremely important to recognize since they may produce fluctuating symptoms or TIAs prior to a devastating stroke. Transient focal symptoms due to an embolus at these sites occur because blood flow reestablishes itself around the embolus.
The symptoms may return in abundance and produce a stroke when the embolus itself causes a thrombus that further occludes the artery. This can occur hours or even days after the embolus has lodged at the site because it did not migrate or lyse.
●Dissection lesions — Dissection lesions at the origin of the petrous portion of the internal carotid artery or at the C1-2 level of the vertebral artery as it enters the foramen transversarium cause symptoms of cerebral ischemia due to low flow or embolism, which occur within minutes, hours, or even days prior to a devastating stroke. Modern neurovascular imaging technology can establish the diagnosis noninvasively. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis" and "Cerebral and cervical artery dissection: Treatment and prognosis".)
Stroke risk stratification — Methods that can reliably assess the risk of stroke after TIA in individual patients would be useful for triaging patients. The discussion that follows applies to the traditional time-based definition of TIA, which is characterized clinically by the temporary nature (<24 hours) of the associated neurologic symptoms.
ABCD2 score — A simple but suboptimal assessment called the ABCD2 score (ie, ABCD squared, for Age, Blood pressure, Clinical features, Duration of symptoms, and Diabetes) was designed to identify patients at high risk of ischemic stroke in the first seven days after TIA (table 2) . Despite the score's simplicity, it is often miscalculated . The ABCD2 score is tallied as follows (calculator 1):
●Age (≥60 years = 1 point)
●Blood pressure elevation when first assessed after TIA (systolic ≥140 mmHg or diastolic ≥90 mmHg = 1 point)
●Clinical features (unilateral weakness = 2 points; isolated speech disturbance = 1 point; other = 0 points)
●Duration of TIA symptoms (≥60 minutes = 2 points; 10 to 59 minutes = 1 point; <10 minutes = 0 points)
●Diabetes (present = 1 point)
Estimated two-day stroke risks determined by the ABCD2 score in the combined derivation and validation cohorts were as follows :
●Score 6 to 7: High two-day stroke risk (8 percent)
●Score 4 to 5: Moderate two-day stroke risk (4 percent)
●Score 0 to 3: Low two-day stroke risk (1 percent)
The ABCD2 score was designed to be used in primary care settings to stratify patients according to stroke risk and thus identify those who required emergency assessment by specialists. However, its predictive performance is not satisfactory. A systematic review and meta-analysis of 29 studies that included over 13,700 patients with TIA found that the ABCD2 score did not reliably distinguish those with a low and high risk of recurrent stroke, or those with TIAs and TIA mimics .
An earlier meta-analysis found that the score performance was poor in settings of low baseline risk and in TIA diagnosed by nonspecialists .
The predictive power of the ABCD2 score is generally lower in hospital settings compared with population-based settings, thus limiting its utility for high-risk populations [67,71,72].
Other risk models — Risk models that combine information from acute DWI, noninvasive angiography, and presumed TIA etiology improve the accuracy of stroke risk prediction after TIA [20,32,49,73-77]. There are a number of examples:
●Several scores are based upon the conventional ABCD2 score:
•The Clinical- and Imaging-based Prediction (CIP) model incorporates diffusion-weighted MRI findings with a dichotomized ABCD2 score .
•The ABCD2-I score adds information about brain infarction on diffusion-weighted MRI or CT .
•The ABCD3-I score assigns points for an earlier TIA within seven days of the index event and further incorporates data from initial diagnostic brain and carotid imaging .
●The Canadian TIA Score (table 3) estimates the probability of stroke within seven days of a TIA and is based upon nine items from the history and examination and four items from investigations that were correlated with having an impending stroke . The total score ranges from -3 to 23. In the derivation study, scores ≤5 were associated with a low risk (≤0.5 percent) of subsequent stroke, while scores from 6 to 9 were associated with an intermediate risk (approximately 1 to 3 percent), and scores ≥10 were associated with a high risk (≥5 percent). In a prospective cohort study of over 7000 patients with TIA, the Canadian TIA Score was more accurate compared with the ABCD2 or the ABCD2-I for predicting subsequent stroke or carotid artery revascularization .
●The Recurrence Risk Estimator (RRE) score combines clinical (recent history of stroke or TIA plus admission stroke subtype) and imaging information (location, multiplicity, distribution, and age of brain infarcts)  for predicting recurrent stroke following TIA with infarction [80,81]. As mentioned above, time-based TIA associated with acute brain infarction is a high-risk condition, and the RRE is the only predictive score that can be used to further stratify the risk in this particular population. The score identifies subsets of patients with a seven-day stroke risk that is as low as 1 percent and as high as 40 percent. The RRE score was externally validated in a multicenter cohort of over 1400 patients with acute ischemic stroke .
Additional research and validation of these models is needed to determine whether these stroke risk stratification models have any utility for clinical practice. The requirement for MRI limits the widespread applicability of advanced risk prediction models.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Transient ischemic attack (The Basics)")
●Beyond the Basics topic (see "Patient education: Transient ischemic attack (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Time-based definition – The classic, time-based definition of transient ischemic attack (TIA) is a sudden onset of a focal neurologic symptom and/or sign lasting less than 24 hours, caused by a transient decrease in blood supply to the brain, spinal cord, or retina. Although still widely used, this classic definition is inadequate because even relatively brief ischemia can cause permanent neurologic or retinal injury. A substantial proportion of patients with a classically defined TIA (<24 hours in duration) have corresponding ischemic lesions on diffusion-weighted or perfusion-weighted magnetic resonance imaging (MRI) that could explain the transient clinical manifestations. The associated infarctions are often very small. (See 'Traditional time-based definition of TIA' above.)
●Tissue-based definition – The tissue-based definition of TIA is defined as a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. Defining TIA by the absence of infarction means that the end point is biological (tissue injury) rather than arbitrary (24 hours). In addition, this tissue-based definition encourages the use of neurodiagnostic tests to identify brain injury and its cause. (See 'Tissue-based definition of TIA' above.)
●Mechanisms – The symptoms of a TIA depend in part upon the pathophysiologic subtype, which are divided into three main mechanisms (see 'Mechanisms and clinical manifestations' above):
•Embolic TIA, which may be artery-to-artery, or due to a cardioaortic or unknown source. (See 'Embolic TIA' above.)
•Lacunar or small penetrating vessel TIA. (See 'Lacunar or small vessel TIA' above.)
•Large artery, low-flow TIA. (See 'Low-flow TIA' above.)
●Neurologic emergency – TIA is a neurologic emergency. Therefore, the initial evaluation of suspected TIA and minor ischemic stroke requires urgent evaluation (algorithm 1). (See 'Urgency of evaluation' above and "Initial evaluation and management of transient ischemic attack and minor ischemic stroke", section on 'Urgent investigations'.)
●Clinical features and diagnosis – The diagnosis of TIA is based upon the clinical features of the transient attack and the neuroimaging findings. (See 'Diagnosis' above.)
•Typical TIAs – Typical TIAs are characterized by transient, focal neurologic symptoms that can be localized to a single vascular territory within the brain, including one or more of the following (see 'Typical TIA' above):
-Transient monocular blindness (amaurosis fugax)
-Aphasia or dysarthria
-Hemiparesis and/or hemisensory loss
•Atypical TIAs – Atypical spells suggestive of TIA (table 1) may be less likely to have an ischemic cause, but atypical TIAs characterized by negative focal symptoms (where "negative" indicates a loss of some neurologic function) have similar short- and long-term risks of subsequent ischemic stroke, as do patients with typical TIAs, and should therefore be investigated and treated as true TIAs. (See 'Atypical TIA' above.)
●Differential diagnosis – The differential diagnosis of TIA is summarized in the table (table 1) and discussed in detail separately. (See "Differential diagnosis of transient ischemic attack and acute stroke".)
●Risk of stroke – Both traditionally defined TIA (ie, time-based, lasting <24 hours) and minor ischemic stroke are associated with a high early risk of recurrent stroke. The stroke risk in the first two days after TIA is approximately 1.5 to 3.5 percent. The ABCD2 score (table 2) was designed to identify patients at high risk of ischemic stroke in this time period, but its predictive performance is not optimal. Risk stratification models that combine information from brain imaging, vascular imaging, and presumed TIA etiology in addition to the clinical ABCD2 score may improve the accuracy of stroke risk prediction after TIA. (See 'Risk of recurrent stroke' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges J Philip Kistler, MD, Hakan Ay, MD, and Karen L Furie, MD, MPH, who contributed to an earlier version of this topic review.
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