Transient Ischemic Attack

Tra n s i e n t I s c h e m i c A t t a c k Reviewing the Evolution of the Definition, Diagnosis, Risk Stratification, and Management for the Emergency Physician Matthew S. Siket,

a MD, MS ,

Jonathan A. Edlow,

MD

b,

*

KEYWORDS  Transient ischemic attack  Emergency medicine  Risk stratification  Diagnosis  Management KEY POINTS  Take a careful history to establish the abrupt onset of symptoms that fit within a particular cerebrovascular territory, which is the cornerstone of making the diagnosis of TIA.  If the neurologic examination has not completely normalized, treat as a stroke not a TIA.  All patients diagnosed with a TIA should receive some form of antiplatelet therapy.  Because approximately 5% of patients with TIA will have a stroke within 48 hours of the TIA, a rapid workup and implementation of treatments are crucial to reducing that stroke risk.  The only time it is truly safe to discharge patients with TIA is if they do not have an acutely interventional lesion (eg, carotid stenosis or atrial fibrillation). If this workup can be done in the ED or an observation unit, strongly consider inpatient evaluation.

BACKGROUND Introduction

A transient ischemic attack (TIA) is an episode of reversible neurologic deficit caused by temporary focal central nervous system hypoperfusion. In many cases, the symptoms will resolve by the time patients first see the physician; therefore, the diagnosis requires a careful history. TIA is a medical emergency. TIA and ischemic stroke are parts of the same continuum of acute cerebrovascular syndrome (ACVS) just as angina and acute myocardial infarction are part of the continuum of acute coronary

a

Department of Emergency Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA; b Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA * Corresponding author. E-mail address: [email protected]

Emerg Med Clin N Am 30 (2012) 745–770 doi:10.1016/j.emc.2012.05.001 0733-8627/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved.

emed.theclinics.com

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syndromes. Because patients with TIA in the emergency department (ED) have a high risk for stroke within the next 48 hours, it is imperative for the clinician to recognize this golden opportunity to prevent a disabling stroke, the fourth leading cause of death and highest cause of disability in the United States.1 This article reviews our conceptual understanding of TIA, its definition, diagnosis, ways to stratify stroke risk, the acute management and disposition in the ED, and the potential future role of diagnostic biomarkers. History and Definition

The concept of TIA dates back to our earliest understanding of the cerebral vasculature. Sir Thomas Willis, credited with coining the term neurology and describing the vascular circle at the base of the brain that bears his name, is also considered the first to write about warning spells of impending cerebral dysfunction. In 1679 he wrote: “the irradiation of the spirits is wont to be interrupted with little clouds, as it were, scattered here and there, but in the former, the same is forthwith wholly darkened and undergoes total eclipse.”2 Embolic sources were apparent even then because he described “extraneous particles” in the blood as a cause.2 Similar entities are mentioned in medical texts during the eighteenth and nineteenth century, but it was not until the 1950s when the clinical phenomenon became better recognized. C. Miller Fisher described “prodromal fleeting attacks of paralysis, numbness, tingling, speechlessness, unilateral blindness, or dizziness” often preceded and warned of impending strokes in patients with carotid artery disease.3 The name TIA emerged in 1965, at the fourth Princeton Cerebrovascular Disease Conference, after extensive discussion at earlier conferences in 1954 and 1956.4 The classic definition of TIA as “focal cerebral dysfunction of an ischemic nature lasting no longer than 24 hours with a tendency to recur” involves an arbitrary time limit that was agreed on by an ad hoc committee in 1975 and endorsed by the World Health Organization in 1988.5 This definition persisted for many years despite the knowledge that most TIAs last less than 1 hour. In an era before magnetic resonance imaging (MRI), thrombolytic treatment of ischemic stroke, and a better understanding of the hyperacute risk of stroke following TIA, this older definition sufficed. However, in an era marked by these 3 realities, a plea for a modernized tissue-based rather than time-based definition was formally made in 2002 and eventually endorsed by the American Heart Association/American Stroke Association (AHA/ASA) in 2009.6 Thus, the current definition of TIA is “a transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction.”7 Importantly, the element of time is no longer a component of the definition (Box 1). The revised tissue-based definition fragmentized the clinical entities previously referred to as TIA and created a diagnostic dilemma in cases of transient symptoms with imaging evidence of infarction. A source of debate, it remains unresolved whether this is better classified as TIA, ischemic stroke, or a distinct entity unto itself. It has been proposed that transient symptoms with infarction (TSI) should be operationally considered distinct, which is akin to unstable angina in the spectrum of acute coronary syndrome.8 Collectively, the spectrum of ACVS includes TIA, TSI, and ischemic stroke.

Box 1 Revised definition of TIA endorsed by the AHA/ASA “A transient episode of neurologic dysfunction caused by focal brain, spinal cord, or retina ischemia, without acute infarction.”7

Transient Ischemic Attack

Epidemiology

The incidence of TIA in the United States is estimated to be between 200,000 and 500,000, with a prevalence of approximately 5 million people.9 More than one-third of patients will fail to seek medical attention within the first 24 hours of the event.10 TIAs are diagnosed in approximately 0.3% of ED visits.11 Men are more likely than women and African Americans are more likely than Caucasians to experience a TIA.12,13 TIAs were found to be more common among lower-income individuals and those with fewer years of education in one study.10 Regardless of ethnicity, gender, or socioeconomic status, TIA incidence increases exponentially with advancing age.13 Stroke Risk

Overall, stroke is preceded by a TIA in 12% to 30% of patients and a quarter of these will occur shortly after the TIA.14,15 For decades, it was clear that the long-term (3–5 years) outcome of ischemic stroke following TIA was approximately 30% to 40%. However, in 2000, new data suggested that much of this risk is front loaded in the first hours to days after the TIA.16 The risk of stroke is highest within the first 24 hours and decreases steadily thereafter.17 Roughly 11% of patients that experience a TIA will suffer a disabling stroke within 90 days and, of those, half will do so within the first 48 hours following the TIA.18 Furthermore, stroke risk has been shown to be dependent on the underlying pathologic condition that caused the TIA. Hemispheric TIA from tight internal carotid artery (ICA) stenosis is associated with the highest risk of stroke (20.0% at 3 months) compared with other causes (5.7%), such as intracranial small vessel disease and cardioembolism.19 Causes

TIAs and ischemic strokes share the same list of causes, most commonly, the embolic or thrombotic consequences of atherothrombotic disease. When a vascular lesion is found, approximately 25% are caused by thrombotic or embolic complications of atheroma in large- to medium-sized arteries; 25% by intracranial small vessel disease; 20% by cardioembolism; and 5% from less-common causes, such as arterial dissection and hypercoagulable states.20 Unfortunately, in one-quarter to one-half of cases, no clear vascular mechanism is found.21,22 Whether this signifies a lack of sensitivity of routine diagnostic tests or confounding by the presence of TIA mimics remains to be determined. CLINICAL PRESENTATION

When approaching patients with symptoms suggestive of a TIA, the physician’s first objective is to determine whether the described episode is consistent with TIA or not. Misdiagnosis rates among emergency physicians has been reported to be as high as 60%,23 and discordance among neurologists in the diagnosis of TIA by history is thought to be between 42% and 86%.24,25 Moreover, one recent study found that agreement in the diagnosis of TIA was low even among stroke-trained neurologists, emphasizing its subjectivity.26 Onset is characteristically sudden; gradual or marching progression of symptoms is unusual. Symptom duration is usually brief, with 60% of events lasting less than 1 hour.27 History should be directed at ascertaining the abruptness of the onset and the duration of the symptoms. Another useful part of the history is to try to distinguish negative symptoms, which suggest ischemia or infarction, from positive symptoms, which suggest migraine or seizure. Negative symptoms include the loss of sensation,

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movement, or speech; positive symptoms include tingling, abnormal movements, or flashing lights. TIA is a focal process; ideally, one should be able to name the artery whose territory is ischemic. Nonfocal signs and symptoms, including loss of consciousness, confusion, generalized weakness, lightheadedness, or incontinence, are rarely caused by TIAs and do not seem to predict future serious vascular events.28 In particular, headaches, dizziness, and involuntary movements were independently predictive of discordant diagnoses of TIAs between emergency physicians and neurologists in one recent study.29 Although pain is not a typical symptom associated with TIA, unilateral neck pain with focal neurologic findings should raise suspicion for cervical artery dissection. Carotid artery dissection is often associated with an incomplete Horner syndrome and is a leading identifiable cause of stroke in patients aged younger than 45 years.30 Differentiating TIA from Mimics

TIA can be difficult to distinguish from the many mimics that can cause similar symptoms, such as complicated migraine, seizure with or without Todd paralysis, hypoglycemia or other metabolic derangement, hemorrhage, mass lesion, neuropathy, vasculitis, acute vestibular syndrome, and psychogenic causes. Epileptic seizures and migraine headaches were shown to account for 44% and 24% of mimics respectively in one study.31 Although not always present, the report of a preceding aura is helpful to distinguish these alternative diagnoses from TIA. Careful attention to the details of the history mentioned earlier may help to distinguish TIA from mimic. Special Considerations

Amaurosis fugax, or transient monocular blindness, is a form of anterior circulation TIA caused by ischemia of the ophthalmic branch of the distal internal carotid artery. Classically, patients describe vision loss as though a curtain were being lowered over the affected eye, although it can also present as a clouding or darkening of the visual field. This condition must be explicitly differentiated from hemianopia (by visual field testing), which some patients incorrectly think is a problem with one eye. Binocular diplopia, on the other hand, usually points to a posterior circulation lesion. Posterior circulation TIAs originating from the vertebrobasilar system account for roughly 20% of all TIAs, whereas the anterior circulation accounts for 80%.32 Posterior circulation symptoms include vertigo, ataxia, nausea and vomiting, and, less commonly, dysarthria, dysphagia, and diplopia. Isolated dizziness, vertigo, or imbalance has been shown to be ischemic in cause in only 3% of patients (and only 0.9% if the dizziness was an isolated symptom).33 However, in one small study, this proportion was 25% among elderly patients.34 Transient global amnesia was previously thought to be a type of TIA affecting predominantly middle-aged or elderly persons for a period usually lasting 6 to 24 hours.20 Although still poorly understood, current theories support nonischemic causes, such as temporal lobe seizures, migraines, stress-related excitotoxic neurotransmitter release, or idiopathic hypoperfusion of the hippocampus.35,36 DIAGNOSTIC EVALUATION History

The diagnosis of TIA is clinical, although the new definition implies that brain imaging is negative for infarction. Although it can be challenging for patients to accurately describe neurologic dysfunction, the history should focus on establishing whether

Transient Ischemic Attack

or not patients have the abrupt onset of focal neurologic deficits. A nationwide survey found that only 8% of laypersons were able to correctly define or identify one common symptom of TIA, so asking patients about specific associated symptoms is often necessary.10 In addition to obtaining a detailed description of the onset, character, and duration of symptoms, it is important to consider the patients’ age and comorbidities, such as diabetes, because they are key components of risk-stratification tools that are discussed later. The clinician should try to tease out these details of the history: was the numbness more like the loss of sensation when the dentist gives you Novocain (negative) or the pins and needles when your leg falls asleep (positive)? Physical Examination

It is important that the physical examination accurately assess whether baseline neurologic function has been restored. It was recently shown that more than 20% of patients referred to a same-day TIA clinic with reportedly resolved symptoms had persistent deficits on the neurologist’s assessment.37 A full neurologic examination should be performed, including the assessment of cranial nerves, visual fields, language, level of alertness and orientation, and cerebellar and sensorimotor function. The National Institutes of Health Stroke Scale (NIHSS) is a thorough and standardized tool useful in these patients. NIHSS certification is free and ensures accurate assessment (can be performed at http://nihss-english.trainingcampus.net/uas/modules/ trees/windex.aspx). The NIHSS has a predilection for detecting anterior circulation disruptions, so additional testing of the posterior territories should be performed in patients reporting vertiginous or ataxic symptoms. It is also helpful to perform fundoscopy, particularly in patients with visual complaints, to assess for retinal plaques and pigmentation. Auscultation of the neck for carotid bruits and the heart for valvular and structural heart lesions is important and should be documented. Laboratory Testing

Routine laboratory testing is low yield, although it is reasonable to obtain a finger stick glucose, serum chemistry panel, and complete blood count to aid in excluding mimics and identifying uncommon causes of thrombosis, such as polycythemia vera.7 Despite their low yield, coagulation studies are currently recommended by the AHA/ASA (class IIa, level B).7,38 It remains to be determined whether there is a select role for proinflammatory or thrombotic markers, including C-reactive protein (CRP), erythrocyte sedimentation rate, and d-dimer in TIA, but their use is not considered routine. In patients admitted to the hospital or observation units, a fasting lipid profile is considered appropriate, although these do not need to be sent from the ED. Cardiac Evaluation

Cardiac evaluation is important in patients with TIA because the heart is a common source of emboli. All patients should have an electrocardiogram (ECG) (class I, level B) to assess for atrial fibrillation, left ventricular aneurysm, or recent myocardial infarction.7,39 Approximately 2% of patients with TIA will have new-onset atrial fibrillation.40 Prolonged telemetry monitoring is useful in patients with an unclear TIA cause after neuroimaging and ECG. Even after 24-hour telemetry or Holter monitoring, an added 4 days of outpatient Holter monitoring has been shown to reveal paroxysmal atrial fibrillation in an additional 14% of patients.41 Echocardiography should be considered when no other cause has been found. Transthoracic echocardiography (TTE) is more readily obtained in the ED and is useful in detecting large valvular lesions; intracardiac thrombus; and foci for thrombi, such as focal wall motion abnormalities, aneurysms, and other causes of turbulent blood flow.

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However, only 3% of TTEs in patients with stroke or TIA reveal a cardioembolic source in patients lacking other signs of heart disease.42 Transesophageal echocardiogram (TEE) is more sensitive for the detection of aortic arch atheroma, patent foramen ovale, atrial septal defect, atrial thrombus, and valvular vegetation but is more time consuming, invasive, and requires sedation. Collectively, TTE or TEE in patients with TIA yields a major source of cardioembolism in 10% of patients and a minor source in 46%.43 In cryptogenic stroke and TIA, TEE uncovered potentially treatable embolic sources in 61% of patients.44 Brain Imaging

The new tissue-based definition of TIA was generated out of a wealth of data showing that 30% to 50% of patients with traditionally defined TIAs have evidence of infarction on MRI.45–47 Thus, the AHA/ASA currently recommends that all patients with TIA undergo emergent neuroimaging within 24 hours of symptom onset (class I, level B).47 MRI is the preferred modality if available. MRI with diffusion-weighted imaging (DWI) is far more sensitive to infarction (especially early in its course) than computed tomography (CT) (Figs. 1 and 2).48 Reports on the sensitivity of CT to detect acute infarcts range from 4% to 34%.49,50 DWI detects areas of restricted diffusion consistent with cytotoxic edema formation in the ischemic brain, making it the clearly superior imaging modality. However, MRI has several restrictions and is contraindicated in approximately 10% of patients.51,52 Additionally, only 39% of US EDs have 24-hour access to MRI,53 and only between 5% and 15% of health care providers use MRI as the first-line imaging modality of choice in evaluating TIA.11,54 Despite its limitations, CT remains the most common neuroimaging study obtained in patients with TIA presenting to the ED, reportedly performed in 56% to 92% of cases.11,54

Fig. 1. This diffusion-weighted image reveals multiple punctate foci of restricted diffusion consistent with acute infarction. This patient experienced transient symptoms and had an National Institutes of Health Stroke Scale of zero in the emergency department, indicating transient symptoms with infarction.

Transient Ischemic Attack

Fig. 2. Computed tomography and diffusion-weighted images from a patient with a prior right parieto-occipital infarct presenting with transient symptoms and found to have an acute infarct in the adjacent territory.

Determining ways to improve the predictive ability of CT for early stroke risk is an area worthy of further research. Vascular Imaging

Nearly half of the patients with TIA with DWI lesions have stenosis or occlusion of either extracranial or intracranial large arteries, suggesting that vascular imaging is imperative in the acute evaluation of TIA.55 Presently, routine noninvasive cervicocephalic vessel imaging is recommended by the AHA/ASA as part of the acute evaluation of TIA (class I, level A).7 This imaging can be performed by ultrasound using carotid duplex and transcranial Doppler (TCD) or with noninvasive CT or MR angiography (MRA), technologies that have largely supplanted the use of traditional catheterbased cerebral angiography. Advantages and disadvantages of each vascular imaging modality are listed in Table 1. Carotid duplex ultrasound detects significant (>50%) stenosis of the extracranial portion of the ICA with sensitivity and specificity of 88% and 76% respectively.56 Advantages include its low cost, ease of use, widespread availability, and lack of radiation or contrast. The disadvantages include its insensitivity in detecting arterial dissection and complex but nonflow limiting lesions, operator dependence, and the inability to evaluate the intracranial ICA. TCD and transcranial color Doppler ultrasonography can reliably exclude intracranial stenosis in both the anterior and posterior circulation, with a reported negative predictive value of 86%.57 TCD was easily performed within 4 hours of presentation to a high-volume TIA clinic and was found to be independently predictive of recurrent vascular events.58 Contrast-enhanced MRA detects significant supra-aortic extracranial stenosis with a sensitivity between 82% and 92% and specificity between 80% and 97%.55,59 Unenhanced time-of-flight sequences provide a reasonable option in those to whom gadolinium cannot be safely administered. MRA performs similarly to TCD in excluding intracranial stenosis, with a reported negative predictive value of 91%.57 CT angiography (CTA) is widely available in most EDs and can be performed at the time of the initial unenhanced CT, adding only a few minutes to the total scan

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Table 1 Comparison of NPV for various vascular imaging modalities in excluding carotid stenosis greater than 50% Test

NPV (%)

Advantages

Disadvantages

Duplex US

9156

Low cost No IV contrast

Does not visualize intracranial portion of ICA Insensitive for dissection 24-hour availability variable Can miss an ulcerated, nonobstructive plaque

CTA

9760

Easily obtainable and widely available Provides detailed images of cervical and cerebral vessels Sensitive for dissection

Additional radiation exposure Requires IV contrast Some bone averaging at skull base

MRA

9959

Provides detailed images of cervical and cerebral vessels TOF sequences can obviate contrast if contraindicated

Expensive Time consuming Contraindicated in those with indwelling pacemakers, implants, and so forth ED availability limited

Abbreviations: CTA, CT angiography; IV, intravenous; NPV, negative predictive value; TOF, time of flight; US, ultrasound.

time (Fig. 3). It has been reported to achieve a 97% negative predictive value for excluding significant (50%–99%) ICA stenosis compared with traditional angiography.60 Moreover, CTA performed on 64-slice CT scanners has been shown to provide near equivalent diagnostic information to digital subtraction angiography while imaging the cerebral vasculature with one fixed dose of contrast.61 Intracranial arterial occlusion on CTA has been shown to be an independent predictor of poor outcome

Fig. 3. Coronal computed tomography angiography image from a patient with critical internal carotid artery stenosis (red arrow) and calcified atherosclerotic plaque (green arrow).

Transient Ischemic Attack

after stroke and TIA, and most recently CT/CTA abnormalities were found to be equivalent in predicting 90-day stroke recurrence after TIA and minor stroke.62–64 CTA also reliably excludes cervical vessel dissection. Limitations include the need for intravenous contrast and the additional radiation, which has been shown to be between double and triple the dose of a standard CT brain (1.7–2.7 mSv to 4.7–5.4 mSv for CT head and neck).65 The role of perfusion imaging has been explored in TIA but is currently not considered part of routine care. Studies have shown that MR perfusion weighted imaging (PWI) abnormalities are present in 30% to 40% of patients with TIA, and isolated perfusion abnormalities in an otherwise normal MRI are present in 14% to 16% of cases.66–69 Furthermore, CT perfusion has recently been shown to detect abnormalities in onethird of the patients with TIA, which was predictive of in-hospital adverse events, including recurrent TIA and stroke, and was independent of DWI lesions or other traditional risk-stratification tools.70 The current opinion in the neurology community supports PWI as a complimentary tool to DWI in the evaluation of TIA, and at least one study has shown perfusion abnormalities to be predictive of ischemic recurrence at 1 week.71,72 RISK PREDICTION

There have been numerous attempts over the past 20 years to create a validated riskstratification tool that is easy to apply and provides clinicians with a realistic estimate of stroke risk after TIA. The first seems to be the Stroke Prognosis Instrument published by Kernan and colleagues73 in 1991. This tool was followed by Hankey and colleagues74 in 1992, then the California Score in 2000,16 and the ABCD score in 2005.75 The ABCD2 score published in 2007 represents the combined efforts of the authors of the California and ABCD scores and has demonstrated the best discriminative predictive ability. It stratifies patients as low, moderate, or high risk of stroke following TIA at 2, 7, and 90 days.76 Table 2 lists the ABCD2 score and its predictive ability at 2, 7, and 90 days compared with the California and ABCD scores in Table 3. Although the ABCD2 score has raised awareness of the urgency of TIA evaluation in the ED, little consensus exists as to its proper implementation. Since its original publication, several external validation studies have shown mixed results.77–89 Some have argued that the value of the ABCD2 score is in its discriminative ability to differentiate true transient ischemic events from mimics.81 Others have suggested that the ABCD2 score does not predict who will have an infarct in the short-term but rather in which patients the infarct is likely to be severe and disabling.80

Table 2 The ABCD2 score Points A 5 Age >60 y

1

B 5 Blood pressure >140/90

1

C 5 Clinical features: unilateral weakness (2), speech difficulty without weakness (1)

2

D 5 Duration: >60 min (2), 10–59 min (1), <10 min (0)

2

D 5 Diabetes

1

Total

7

Data from Johnston SC, Rothwell PM, Nguyen-Huynh MN, et al. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 2007;369:283 92.

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Table 3 Summary of stroke risk using early clinical prediction rules Stroke Risk (%) California

ABCD

ABCD2

ABCD2

ABCD2

Points

90 d

7d

2d

7d

90 d

Probability

0 1 2 3

0 3 7 11

0 0 0 0

1.0

1.2

3.1

Low

4 5

15 34

2.2 16.3

4.1

5.9

9.8

Mod

6 7

– –

35.5 –

8.1

11.7

17.8

High

Data from Ross M, Nahab F. Management of transient ischemic attacks in the twenty-first century. Emerg Med Clin North Am 2009;27:51–69.

As with all of the early clinical risk-stratification tools, the predictive ability of the ABCD2 score is limited by not including information about underlying disease mechanism. The utility of clinical risk prediction in EDs that routinely perform brain and vessel imaging has been called into question and it has been criticized for being misleadingly reassuring.90 Perhaps most concerning, one recent study found that the ABCD2 score calculated in several EDs in a cohort of 2056 consecutive patients with TIA was lower than the score calculated in follow-up by the coordinating center in one-third of patients.89 This discrepancy was most frequently caused by emergency-physician inconsistency in scoring unilateral weakness when it was reported in the patient’s history but absent on physical examination. At best, the ABCD2 score is a tool to provide a general gauge at overall short-term stroke risk. In no way should it supersede physician judgment, and the authors advise against using it alone as a basis for determining disposition in the ED. This topic is discussed further in the disposition section. To enhance the discriminative ability of the ABCD2 score, several imagingenhanced scores have been developed (Table 4), all of which at least modestly improve the predictive ability of the clinical score. Previous work has shown that imaging negative TIA as a whole is a fairly benign condition. Patients with TIA with normal DWI have a 0.4% incidence of stroke at day 7.86 Additionally, combining normal DWI and an ABCD2 score less than 4 achieved a sensitivity of 100% in predicting the absence of stroke at 7 days in multiple studies.51,91 Conversely, patients with infarct-positive TIA confer a 20-fold higher risk of stroke at 7 days than imaging negative TIA and 5- to 10-fold higher than that of recurrent disabling stroke.92 The Clinical and Imaging-based Predictive model and the ABCD2-I, ABCD3-I, and ABCDE1 scores all incorporate DWI findings into stroke-risk calculation.45,46,51,93 Only the ABCD2-I score considered CT imaging data and found that it was equal to DWI in improving the predictive power of the ABCD2 score (area under the curve [AUC] 0.78). Table 5 separates estimated 7-day stroke risk by imaging findings by modality and trichotomized ABCD2 score. Although the addition of early DWI has aided the overall short-term stroke-risk prediction in patients with TIA, it adds little insight as to the underlying vascular mechanism responsible for the event and, accordingly, is limited in prognosticating future events. Etiologic algorithms, such as the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria, SSS TOAST, and the automated Causative Classification System,

Table 4 Summary of recent imaging-enhanced prediction rules

Model/ Score

Published (Date)

Number of Patients

Total Points

Follow-up (Days)

Pooled C Statistic or Area Under the Curve (AUC)

CIP51

1/09

601

71I

7

0.81

DWI

No

Scores 1 point for DWI abnormalities and a dichotomized ABCD2 score (<4 or 4) http://cip.martinos.org

RRE97

1/10

257

7

7, 14, 90

0.85

DWI

Yes

In patients with TSI, scores 1 point each for prior stroke in past month, CCS subtype off LAA or other causes and DWI lesion characteristics

ABCD2I45

7/10

4574

10

7, 90

0.80

DWI or CT

No

Scores 3 points for the addition of abnormal imaging, defined as acute or old infarct on CT or DWI lesion

ABCD3I46

11/10

3886

13

2, 7, 28, 90

0.79

DWI 1 carotids

Yes

Scores 2 additional points for DWI lesions, dual event within the preceding 7 days, and 50% ipsilateral carotid stenosis using Duplex US, CTA, or MRA

ABCDE193

1/12

248

13

90

0.67

DWI

Yes

Scores 3 points for DWI lesions and LAA, 1 point for cardioembolism, small arterial occlusion, or undetermined causes using TOAST criteria

Imaging Modality

Considers Mechanism?

Summary

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Abbreviations: AUC, area under the curve; CCS, Causative Classification System; CIP, Clinical and Imaging-based Predictive model; LAA, Large Artery Atherosclerosis; RRE, recurrence risk estimator; TOAST, Trial of Org 10172 in Acute Stroke Treatment; US, ultrasound.

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Table 5 Seven-day stroke risk by imaging modality and ABCD2 score Imaging Modality

Infarction Present?

ABCD2 Score

7-Day Stroke Risk (%)

Upper Limit 95% CI

CT

No

0–3 4–5 6–7 0–3 4–5 6–7

0.9 3.0 7.3 3.9 12.9 21.0

2.6 4.9 12.2 11.5 19.6 33.6

0–3 4–5 6–7 0–3 4–5 6–7

0.1 0.7 0.4 1.8 7.5 12.5

0.5 1.4 2.1 4.6 10.4 18.6

Yes

MRI

No

Yes

Abbreviation: CI, confidence interval. Data from Giles MF, Albers GW, Amarenco P, et al. Early stroke risk and ABCD2 score performance in tissue- versus time-defined TIA. Neurology 2011;77:1222–8.

have been developed to ease the determination of stroke cause and improve interrater agreement.94–96 A Web-based recurrence risk estimator score was developed specifically for TSI because these individuals have been shown to be at the highest risk of stroke in the short-term.97,98 The AHA/ASA and National Institutes for Health and Clinical Excellence (NICE) guidelines now incorporate the ABCD2 score and imaging findings into acute management and disposition recommendations in TIA.7,99 Regardless of whether a newer mechanism-driven or imaging-enhanced risk-prediction tool is used, there is general consensus that a complete etiologic workup should be performed as urgently as possible. The distinction between accurate risk stratification and completing the etiologic workup up front is blurred, calling into question where to draw the line in the ED. It has been suggested elsewhere, and remains the opinion of these authors, that taking a work-up-everybody policy by performing as much of an etiologic workup in the ED as logistically possible is the best way to ensure that patients receive optimal care during the period of highest stroke risk.90 This policy could mean hospitalizing patients or performing the evaluation in the ED. If this is not logistically feasible in a given location, then the physician should consider using the ABCD2 score and organize the workup as per the AHA 2009 guidelines.7

MANAGEMENT General Considerations

The primary goals in patients with TIA and TSI are to optimize cerebral perfusion to the ischemic tissue and to prevent a subsequent more disabling stroke. Positioning the patient with the head of the bed flat has been shown (by TCD) to increase cerebral perfusion by 20% compared with a 30 incline.100 This simple step should be done routinely unless contraindicated. As in ischemic stroke, it is generally a good idea to maintain euvolemia, and all patients with TIA should have intravenous access while in the ED. Conflicting data exist as to the utility of supplementary oxygen in patients with cerebral ischemia but is generally not recommended unless patients are hypoxic.101,102

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Antihypertensive Treatment

Permissive hypertension is the strategy of avoiding aggressive treatment of elevated blood pressure in the acute setting. It is thought that patients with cerebral ischemia may have impaired cerebral autoregulation and require higher mean arterial pressures to maximize the perfusion of collateral vessels. Current AHA/ASA consensus panel recommends that emergency administration of antihypertensives be withheld unless blood pressure is greater than 220/120 mm Hg.103 Multiple studies have demonstrated worse outcomes after stroke in those treated acutely with blood-pressure lowering agents.104,105 Unlike stroke, patients with TIA are probably less likely to experience drops in cerebral perfusion pressure; to date, outpatient oral antihypertensive treatment initiated during the initial evaluation has not been associated with worsened outcomes.106,107 Currently, the AHA/ASA recommends initiating antihypertensive medications in patients who remain stable beyond the first 24 hours following a TIA or stroke.108 Therefore, prescribing antihypertensive medication is not generally an ED issue, unless one is discharging a patient from an ED-based observation unit. The target blood pressure after the first 24 hours remains to be determined, but a reduction of 10/5 mm Hg or normalization to less than 120/80 using a diuretic or angiotensin-converting enzyme inhibitor is supported.108 Antiplatelet Therapy

Absent a specific contraindication or a cardioembolic source that necessitates full anticoagulation, every patient with TIA should receive antiplatelet therapy. The Food and Drug Administration has approved 4 antiplatelet agents for the prevention of vascular events following TIA or stroke. These agents include aspirin, aspirin/dipyridamole combination, clopidogrel, and ticlopidine, which have collectively demonstrated an average reduction of the relative risk of stroke, myocardial infarction, or death of 22%.109 Clopidogrel and aspirin/dipyridamole have demonstrated superiority to aspirin alone, and a head-to-head trial comparing these 2 agents showed similar efficacy and safety profiles.22,110 To date, combination therapy with aspirin and clopidogrel has not demonstrated benefit over clopidogrel or aspirin alone but has shown an increase in bleeding complications and is not routinely recommended.111–113 In some situations in which clopidogrel is indicated for another reason (such as coronary artery disease), aspirin plus clopidogrel may be indicated. Ticlopidine is rarely used because of its side-effect profile. Anticoagulation

For patients with TIA or stroke that is thought to be caused by atrial fibrillation, anticoagulation with warfarin is advised (target international normalized ratio [INR] of 2.5; range 2–3; AHA/ASA class I; level A recommendation).108 Dabigatran is a direct thrombin inhibitor that has demonstrated noninferiority to warfarin in preventing stroke in patients with atrial fibrillation and is a reasonable alternative, although no known reversal agent exists to date.114 If oral anticoagulants are contraindicated, aspirin alone is recommended. See Tables 6 and 7 for pharmacologic recommendations by TIA cause and dosing. Endovascular Treatment of Cervical Carotid Stenosis

In patients with imaging evidence of severe (>70%) carotid stenosis, carotid endarterectomy (CEA) significantly reduces stroke risk.115 Overall stroke risk reduction in these patients is 10% to 15% and seems to be more beneficial in older patients (aged >75 years). A similar benefit seems to exist in patients with 50% to 70% stenosis and the

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Table 6 Management recommendations by TIA or minor stroke cause Cause

Incidence (%)

Large artery w25 atherosclerosis

Management Antiplatelet therapy, and if carotid stenosis >50%, evaluation for endarterectomy to be performed preferably within 2 wk

Small vessel disease

w25

Antiplatelet therapy

Cardioembolic

w20

Anticoagulation

Arterial dissection

w5

Antiplatelet therapy or anticoagulation for 3–6 mo

Hypercoagulable state and inherited thrombophilias Cryptogenic or unknown

Initiate statin therapy, optimization of comorbidities (such as hypertension and diabetes), and risk factor modification

Hematologic workup and condition-specific anticoagulation or antiplatelet therapy w25

Antiplatelet therapy

benefit is greatest if performed within 2 weeks of the sentinel event.115 Carotid angioplasty and stenting is considered a reasonable alternative to CEA, particularly in those considered at high risk for surgical complications.108 Decisions about which method of opening the carotids are beyond the scope of emergency medicine practice.

Table 7 Commonly used medications for stroke prevention after TIA Therapy

Agent

Dose

Indication

Antiplatelet

Aspirin

160–325 mg/d acutely, then 81 mg/d Aspirin 25 mg 1 extended- release dipyridamole 200 mg/d 300 mg/d acutely, then 75 mg/d

All acute TIA

Heparin

Parenteral to target PTT

Warfarin

Dose to target INR of 2–3 150 mg twice daily (renal dose is 75 mg twice daily)

Stuttering TIA or known cardioembolic source or severe large vessel stenosis TIA caused by atrial fibrillation

Aspirin/ dipyridamole combination Clopidogrel Anticoagulation

Dabigatran

Stroke prevention after TIA: better than aspirin alone and equivalent to clopidogrel Stroke prevention in patients with aspirin allergy

TIA caused by atrial fibrillation

Abbreviation: PTT, partial thromboplastin time. Data from Cucchiara B, Kasner SE. In the clinic: transient ischemic attack. Ann Intern Med 2011;154:ITC11-15 [quiz: ITC1–16].

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Lipid Modification

Lowering cholesterol with statins has been shown to reduce the risk of vascular events in patients with TIA and stroke.116 Statins are thought to stabilize atherosclerotic plaques; decrease the intimal-medial thickness of the carotids; and promote antioxidant, antiinflammatory, and antiplatelet effects.22 The current AHA/ASA recommendation is to initiate statins after TIA or stroke for patients with an low-density lipoprotein (LDL) greater than 100 mg/dL with a target goal of an LDL level of less than 70 mg/dL.108 Risk-Factor Modification

Other independent risk factors associated with stroke include cigarette smoking and heavy alcohol consumption. Obese (body mass index >30 kg/m3) patients should be counseled on weight-reduction strategies, although to date no study has demonstrated that weight loss reduces stroke risk. Moderate physical activity has been shown to reduce stroke risk by 20%.117 Special Circumstances

For patients with TIA or stroke secondary to cervical arterial dissection, the AHA/ASA currently recommends antithrombotic treatment for 3 to 6 months. There is no clear consensus whether anticoagulation or antiplatelet therapy is superior; therapy should be individualized. Dissections generally heal with time, but if recurrent cerebral ischemic events occur, endovascular stenting may be considered. For patients with documented patent foramen ovale, the optimal treatment remains in question and is the subject of ongoing investigation. The role of the emergency physician in these cases will be to facilitate appropriate cardiology and neurology referral, although initiating antiplatelet therapy is reasonable with specialty consultation.108 If infective endocarditis is the suspected source of emboli, blood cultures, early antiinfective treatment, and cardiology consultation is indicated.118 Thrombolysis

Rapidly improving symptoms and minor neurologic deficits are considered contraindications to thrombolytic administration, so their use in TIA is not recommended. However, because the risk of stroke following TIA is frontloaded and highest within the ensuing 48 hours, access to recombinant tissue plasminogen activator (rt-PA) is imperative. This point is particularly true in patients with stuttering or crescendo TIAs who experience frequent episodes and carry a more ominous prognosis in the short term. In terms of the time window, one starts the clock from the time when patients were last completely normal; that is, for patients with waxing and waning symptoms, the last time they were totally normal would count for the time window. Patients and caretakers should be cautioned to return immediately if symptoms return so that thrombolysis can be given if indicated. Patients should also be educated about time windows for therapy and how to access 911 to rapidly get to a stroke center. DISPOSITION

Determining which patients to admit to the hospital versus observe in an observation unit or discharge with rapid follow-up is a source of uncertainty and frustration for many emergency physicians. Factors likely to contribute to varying admission thresholds include the ease of access to follow-up testing and neurology consultation, inpatient bed availability, patient expectations, and medicolegal concerns. Some have advocated for admission policies based on the ABCD2 score. In reviewing the cohorts used to create and validate the ABCD2 score, a policy limited to

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admitting only high-risk patients (ABCD2 of 6 or 7) would have resulted in 1012 admissions and the discharge of 106 patients that would go on to suffer a stroke within 2 days.76 Similarly, a policy that mandates admission of all except low-risk patients (all with ABCD2 >3) would have resulted in 3171 admissions, of which 5.4% would progress to stroke within 48 hours. Even with this liberal admission model, 17 patients would have been sent home and experienced strokes within 48 hours as outpatients. This recommendation is the current recommendation of the National Institute for Clinical Excellence, which, in their 2008 publication of the NICE guidelines, endorses outpatient evaluation within 1 week for patients with an ABCD2 score less than 4.99 However, it was recently shown that these patients have similar rates of stroke as patients with an ABCD2 score greater than or equal to 4, so the authors advise against strict interpretation of this recommendation.119 The AHA/ASA supports a more liberal admission threshold, endorsing admission for patients with TIA with an ABCD2 score greater than 2, evidence of focal ischemia, or in any patient in whom rapid follow-up cannot be completed within 2 days as an outpatient. One recent study of 2056 patients found that an ABCD2 score of greater than 2 had a sensitivity of 94.7% and a specificity of 12.5% of predicting stroke at 7 and 90 days after TIA.89 Even with such poor specificity, this model fails to sufficiently capture all patients at the highest short-term stroke risk. Also, in many medical care systems, having the workup accomplished as an outpatient within 48 hours is not logistically feasible. Thus, the authors advise against any disposition policy based solely on the ABCD2 score. The hospital admission of all patients with TIA has been proposed by some because it offers the closest observation of patients during the window of the highest risk of stroke and the best likelihood of access to thrombolysis and advanced diagnostic modalities, including continuous telemetry monitoring. One recent study of 3554 consecutive patients with TIA admitted to a German hospital reported a mean length of stay of 6.5 days, during which the stroke incidence was 1.2%.120 Identifying a more efficient and cost-effective alternative to lengthy admission has been the focus of multiple studies over the past few years. However, some have argued for 24-hour hospitalization of higher-risk patients on the grounds of being cost-effective simply because of the improved access to thrombolytics.121 Others have found that despite increased access to rt-PA, hospitalization was not cost-effective when compared with a same-day TIA clinic evaluation.122 The specialist-assisted triage of patients with TIA to improve the selection of patients warranting hospital admission beyond the ABCD2 score has shown promising results, with 7- and 90-day stroke rates of 1.6% and 2.0% respectively.123,124 These results support ED-based neurology consultation, at least by telephone, before disposition. ED-based observation units (EDOU) are becoming more common. EDOUs allow for accelerated, protocol-driven care, which is amenable to TIA because many patients undergo multiple imaging studies during their etiologic workup. Multiple prospective trials of EDOU-based TIA care determined this strategy to be feasible, time and cost saving, and not associated with higher rates of short-term stroke compared with hospital admission.125–128 Individual EDOU protocols vary but typically involve preadmission physician assessment, CT scan of the brain, ECG, laboratory analysis, and neurology consultation. The use of vascular imaging, MRI, and echocardiography in the observation unit is selective. Rapid-access TIA clinics, such as the ones described in the French SOS-TIA study and the British EXPRESS study, provide outpatient alternatives (24-hour access to TIA clinics) to hospital admission and have been shown to reduce the risk of stroke after TIA by 80%.106,129 They have been shown to significantly reduce overall hospital bed

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days and associated health care costs.107 The cost-effectiveness analysis of the EXPRESS study concluded that their urgent-access clinic saved an average of £624 per patient assessed.107 They offer the advantage of ensuring rapid specialist evaluation, comprehensive testing, and an opportunity for direct referral from the patient’s primary care physician thereby bypassing the ED. Neither of these studies used routine MRI or cardiac echo. Clinics such as these provide a means for the regionalization of TIA management and data collection for research purposes. They are not yet commonplace in the United States, but the results of SOS-TIA and EXPRESS have proven the concept of such clinics. The authors think that the best care is to evaluate all patients with TIA immediately on diagnosis in one or another setting. Risk stratification has begun to encompass the workup. Algorithms, such as the AHA/ASA’s, that recommend select outpatient workup in some patients still advise that the workup takes place within 2 days, the very period of time in which the stroke risk is highest. It seems most logical to simply do the workup at once. The data show that this can be safely and less expensively accomplished as outpatients.90 This approach would correctly identify most patients in need of a specific therapy (eg, a large vessel intervention or anticoagulation) at the time when that treatment is most likely to prevent a second event and would also more accurately classify patients with TIA versus stroke based on the new definition. Figs. 4 and 5 outline the authors’ suggestions for the general approach to patients with TIA in the ED and disposition recommendations. FUTURE DIRECTIONS

If recent history is any indication of future direction, then there will certainly be continued effort in improving stroke-risk prediction after TIA. It is clear that individual stroke risk is best estimated when the TIA cause is known and cerebrovascular disease burden has been assessed with advanced imaging studies. How to best History, physical exam *, a signs, al signs n , FS glucose & vital bas a ic lab a s basic labs

HOB flat, IV fluids (if n ede ne d d) d needed) Permissive Perm rmissive HTN

Evidence Evide d nc n e of Mimi Mimic? m c?

MRI R pre preferred r fe f rr rred test, t st, te t but non-contrast n n-cont no ntrast CT if MRI no n nott ra rrapidly p dl pi d y availab available. able.

Neuroimaging Neuro r ima maging n Yes

No ECG

Manage Mana nage accordingly ord rding n ly

Arr Arrhythmia rrhyth thmia or infarction? inf nfarcti t on? IImaging Im maging n is normal n rm no rmal

IImaging Im maging n shows sho h ws acute t ische h mi m c stro r ke k (TSI) I ischemic stroke

Consult Cons n ul u t ne n neurology uro r logy

* - exam am must m st include mu inc n lude d a careful care r fu ful neurological exam (and ideally, a NIHSS) to document that the patient is neurologically normal; if not, presume acute stroke until proven otherwise.

IImaging Im maging n shows sho h w ICH or oth thermi m mi m c such suc as SDH, othermimic ttumor, tu m r, mo r eetc.

Manage Mana nage accor accordingly

TIIA very lik TIA T likely; l go tto risk stratification and disposition algorithm

Fig. 4. Approach to patients with symptoms suggestive of TIA in the ED. FS, fingerstick; HOB, head of bed; HTN, hypertension; ICH, intracerebral hemorrhage; IV, intravenous; SDH, subdural hematoma.

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Fig. 5. TIA diagnosis likely; disposition from the ED (asterisk).

improve risk estimation when imaging resources are limited in the short-term remains to be determined. Serum biomarkers of cerebral ischemic injury would prove useful in the diagnosis of TIA and have been the source of exhaustive research in recent years. They are low cost, universally available, fast, and easy to interpret. The targets to date have been markers of underlying systemic vascular inflammation, coagulation activation, and neuronal injury. They have been limited by the lack of specificity and challenges created by the blood-brain barrier. Although the troponin of the brain has remained elusive, several have shown promise as potential point-of-care tests to improve TIA diagnosis and risk stratification in the ED.130 CRP is a marker of systemic inflammation and vascular events and has been explored as a tool in TIA with mixed results. One study found that it was independently predictive of stroke at 2 years after TIA and modestly improved the discriminative predictive ability of the ABCD2 score.131 The hypothalamic stress hormone, copeptin, has been similarly explored as a serologic adjunct to the ABCD2 score and demonstrated promising results.132 Lipoprotein-associated phospholipase A2 is a similar marker of vascular inflammation and atherosclerotic plaque instability and was found to be independently associated with vascular events in patients with acute TIA, whereas CRP was not.133 D-dimer and brain natriuretic peptide have been linked to cardioembolic causes of TIA.134 RNA expression in patients with TIA was recently explored using microarrays and yielded a set of 34 promising genes that discriminated TIA from controls with 100% sensitivity and specificity.135 Although not yet applicable to clinical use, this does show promise in the search for serologic surrogates of cerebral ischemia and will certainly continue to be a focus of ongoing research. Use of multi-marker panels to improve collective specificity is a particularly intriguing concept that has already shown utility in distinguishing acute ischemic stroke from mimics.136 The progressive use of imaging will likely continue to be a focus of TIA research. The use of CTA and perfusion imaging in TIA has been reported in a few studies with promising results and is likely to become more common in emergency systems with limited

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access to acute MRI.64,70 As MRI technology continues to evolve, novel imaging sequences that use traces of cerebral injury, such as oxygen extraction and water exchange, appear on the horizon. Perhaps more important than any other endeavor in the short term, creating more widespread, rapid, and cost-efficient outpatient care systems in which to evaluate patients within 48 hours after TIA should be a primary focus for research and investment. This endeavor should of course be done in conjunction with neurologists, stroke experts, and radiologists so that the system that has been developed for chest pain can be rolled out to patients with transient cerebral ischemia. SUMMARY

The evaluation of TIA in the ED is a golden opportunity to prevent a disabling stroke. The greatest risk is in the first 48 hours after the TIA. Clinical risk stratification tools provide a partial estimation of short-term risk and may help differentiate TIAs from nonischemic events. The diagnosis is made based on history, a normal neurologic examination, and neuroimaging with absence of infarction. The 24-hour time window is no longer relevant, and most TIAs last less than 1 hour. Etiologic classification helps to determine patients’ true short-term risk of stroke and helps guide individual therapy. In most noncardioembolic TIAs, single antiplatelet therapy is indicated, whereas anticoagulation should be considered in most cardioembolic TIAs. The authors think that patients with TIA should undergo immediate evaluation and treatment, whether as inpatients or outpatients. Patients with TIA should not be discharged if completion of their etiologic workup cannot be completed within 2 days. Alternatives to hospitalization include EDOUs and rapid-assessment outpatient TIA clinics, both of which are rapidly gaining popularity worldwide. REFERENCES

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