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, 2 large artery atherosclerosis, and an ABCD 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 [41]. 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 [14]. 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 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 12/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate year overall but 5.5 percent per year in those with more than a 75 percent carotid artery stenosis [63]. 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 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 13/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 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. 2 ABCD2 score A simple but suboptimal assessment called the ABCD 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) [67]. 2 Despite the score's simplicity, it is often miscalculated [68]. The ABCD 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) 2 Estimated two-day stroke risks determined by the ABCD score in the combined derivation and validation cohorts were as follows [67]: 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) 2 The ABCD 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 2 29 studies that included over 13,700 patients with TIA found that the ABCD score did not reliably distinguish those with a low and high risk of recurrent stroke, or those with TIAs and TIA mimics [69]. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 14/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate An earlier meta-analysis found that the score performance was poor in settings of low baseline risk and in TIA diagnosed by nonspecialists [70]. 2 The predictive power of the ABCD 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: 2 Several scores are based upon the conventional ABCD score: The Clinical- and Imaging-based Prediction (CIP) model incorporates diffusion-weighted 2 MRI findings with a dichotomized ABCD score [32]. 2 The ABCD -I score adds information about brain infarction on diffusion-weighted MRI or CT [20]. 3 The ABCD -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 [73]. 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 [78]. 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 2 2 Canadian TIA Score was more accurate compared with the ABCD or the ABCD -I for predicting subsequent stroke or carotid artery revascularization [79]. 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) [74] 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 [82]. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 15/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 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." th th The Basics patient education pieces are written in plain language, at the 5 to 6 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 th th sophisticated, and more detailed. These articles are written at the 10 to 12 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) https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 16/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 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 Hemianopia 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.) https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 17/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 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 2 the first two days after TIA is approximately 1.5 to 3.5 percent. The ABCD 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 2 ABCD 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. Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. 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BMJ 2021; 372:n49. https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 23/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate 80. Arsava EM, Furie KL, Schwamm LH, et al. Prediction of early stroke risk in transient symptoms with infarction: relevance to the new tissue-based definition. Stroke 2011; 42:2186. 81. Maier IL, Bauerle M, Kermer P, et al. Risk prediction of very early recurrence, death and progression after acute ischaemic stroke. Eur J Neurol 2013; 20:599. 82. Arsava EM, Kim GM, Oliveira-Filho J, et al. Prediction of Early Recurrence After Acute Ischemic Stroke. JAMA Neurol 2016; 73:396. Topic 1088 Version 24.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 24/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate GRAPHICS Temporal behavior of symptoms in patients with transient ischemic attack (TIA) The probability density function curve of symptom duration for transient symptoms associated with infarction (TSI) indicates the absence of continuity within the first 24 hours. The probability density function is the probability that the variable takes a value in a given interval and is equal to 1 over its entire range of values. The area under curve is almost equal to 1 at around 200 minutes. Also note that the curves for TIA with or without infarction overlap (p = 0.82). The distribution of duration of symptoms as seen here suggests that symptom duration is not a reliable feature to be used for predicting whether a transient neurological spell is associated with infarction. DWI: diffusion-weighted magnetic resonance imaging. Reproduced with permission from: Ay, H, Koroshetz, WJ, Benner, T, et al. Transient ischemic attack with infarction: a unique syndrome. Ann Neurol 2005; 57:679. Copyright 2005 John Wiley & Sons. Graphic 82729 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 25/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Anterior cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 60945 Version 3.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 26/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Middle cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 81813 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 27/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Posterior cerebral artery distribution and signs and symptoms of occlusion Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 60416 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 28/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Superior pontine syndrome Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases, Harrison's Principles of Internal Medicine, 13th ed. McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 53412 Version 1.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 29/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Anatomy of the cerebral arterial circulation Frontal view of the carotid arteries, vertebral arteries, and intracranial vessels and their communication with each other via the circle of Willis. Reproduced with permission from: U acker R. Atlas Of Vascular Anatomy: An Angiographic Approach, Second Edition. Philadelphia: Lippincott Williams & Wilkins, 2006. Copyright 2006 Lippincott Williams & Wilkins. Graphic 51410 Version 6.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 30/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Major cerebral vascular territories Representation of the territories of the major cerebral vessels shown in a coronal section of the brain. Reproduced with permission from Kistler, JP, et al, Cerebrovascular Diseases. Harrison's Principles of Internal Medicine, 13th ed, McGraw-Hill, New York 1994. Copyright 1994 McGraw-Hill Companies, Inc. Graphic 65199 Version 2.0 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 31/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Transient ischemic attack (TIA) and minor ischemic stroke: Rapid overview of emergency management Clinical features 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: Transient monocular blindness (amaurosis fugax) Aphasia or dysarthria Hemianopia Hemiparesis and/or hemisensory loss (complete or partial) Atypical TIAs may present with transient isolated neurologic symptoms: Isolated vertigo Isolated ataxia Isolated diplopia Isolated speech disturbance (slurred speech) without aphasia Isolated bilateral decreased vision Isolated unilateral sensory loss involving only one body part Differential diagnosis Seizure Migraine aura Syncope Transient global amnesia Central nervous system demyelinating disorder (eg, multiple sclerosis) Peripheral vestibulopathy Metabolic disorder (eg, hypoglycemia) Myasthenia gravis Cranial/peripheral neuropathy Cerebral amyloid angiopathy Subdural hematoma Subarachnoid or intracerebral hemorrhage Transient neurologic attack not otherwise specified Immediate treatment while evaluating the ischemic mechanism For patients with TIA or minor, nondisabling acute ischemic stroke (and thus not eligible for thrombolytic therapy or mechanical thrombectomy), start antiplatelet therapy immediately while the evaluation is in progress: Start DAPT (aspirin plus clopidogrel, or aspirin plus ticagrelor) for patients with one of the following: 2 High-risk TIA, defined by an ABCD score 4 https://www.uptodate.com/contents/definition-etiology-and-clinical-manifestations-of-transient-ischemic-attack/print 32/41 7/6/23, 1:06 PM Definition, etiology, and clinical manifestations of transient ischemic attack - UpToDate Time-based TIA with a relevant large artery stenosis or DWI lesion on MRI (if imaging available at this stage) Minor, nondisabling ischemic stroke, defined by an NIHSS score 5 Start aspirin monotherapy for patients who do not meet the above criteria (ie, TIA with an 2 ABCD score <4 and no relevant large artery stenosis or DWI lesion on MRI [if imaging available at this stage]) Once the ischemic mechanism is determined, antithrombotic therapy can be modified as necessary Urgent evaluation