Download Transient Ischemic Attack - Emergency Medicine Clinics of North

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
746
Siket & Edlow
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,
747
748
Siket & Edlow
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.
749
750
Siket & Edlow
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
751
752
Siket & Edlow
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.
753
754
Siket & Edlow
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
Transient Ischemic Attack
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.
755
756
Siket & Edlow
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
Transient Ischemic Attack
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
757
758
Siket & Edlow
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].
Transient Ischemic Attack
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
759
760
Siket & Edlow
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
Transient Ischemic Attack
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.
761
762
Siket & Edlow
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
Transient Ischemic Attack
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
1. Towfighi A, SAver JL. Stroke declines from third to fourth leading cause of death
in the United States: historical perspective and challenges ahead. Stroke 2011;
42:2351–5.
2. Willis T. Instructions and prescripts for curing the apoplexy. in Pordage S (ed):
The London Practice of Physic or the Whole Practical Part of Physic. Dring T,
Harper C, Leigh J, Martyn S 1679.
3. Fisher CM. Occlusion of the internal carotid artery. AMA Arch Neurol Psychiatry
1951;65:346–77.
4. Caplan LR. Transient ischemic attack: definition and natural history. Cerebrovasc Dis 2006;8:276–80.
5. WHO MONICA. Project principal investigators. The World Health Organization
MONICA Project (monitoring trends and determinants in cardiovascular
disease): a major international collaboration. J Clin Epidemiol 1988;41:105–14.
6. Albers GW, Caplan LR, Easton JD, et al. Transient ischemic attack - proposal for
a new definition. N Engl J Med 2002;347:1713–6.
7. Easton JD, Saver JL, Albers GW, et al. Definition and evaluation of transient
ischemic attack. Stroke 2009;40:2276–93.
8. Ay H, Koroshetz WJ, Benner T, et al. Transient ischemic attack with infarction:
a unique syndrome? Ann Neurol 2005;57:679–86.
9. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics–
2010 update: a report from the American Heart Association. Circulation 2010;
121:e46–215.
763
764
Siket & Edlow
10. Johnston SC, Fayad PB, Gorelick PB, et al. Prevalence and knowledge of transient ischemic attack among US adults. Neurology 2003;60:1429–34.
11. Edlow JA, Kim S, Pelletier AJ, et al. National study on emergency department
visits for transient ischemic attack, 1992-2001. Acad Emerg Med 2006;13:
666–72.
12. Hill MD, Yiannakoulis N, Jeerakathil T, et al. The high risk of stroke immediately
after transient ischemic attack: a population-based study. Neurology 2004;62:
2015–20.
13. Kleindorfer D, Panagos P, Pancioli A, et al. Incidence and short-term prognosis
of transient ischemic attack in a population-based study. Stroke 2005;36:720–3.
14. Rothwell PM, Warlow CP. Timing of TIAs preceding stroke: time window for
prevention is very short. Neurology 2005;64:817–20.
15. Hackam DG, Kapra MK, Wang JT, et al. Most stroke patients do not get
a warning: a population-based cohort study. Neurology 2009;73:1074–6.
16. Johnston SC, Gress DR, Browner WS, et al. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000;284:2901–6.
17. Chandratheva A, Mehta Z, Geraghty OC, et al. Population-based study of risk and
predictors of stroke in the first few hours after a TIA. Neurology 2009;72:1941–7.
18. Lisabeth LD, Ireland JK, Risser JM, et al. Stroke risk after transient ischemic
attack in a population-based setting. Stroke 2004;35:1842–6.
19. Calvet D, Touze E, Oppenheim C, et al. DWI lesions and TIA etiology improve
the prediction of stroke after TIA. Stroke 2009;40:187–92.
20. Pendlebury ST, Giles MF, Rothwell PM. Causes of transient ischemic attack and
stroke. In: Pendlebury ST, Giles MF, Rothwell PM, editors. Transient ischemic
attack and stroke: diagnosis, investigation and management. 1st edition. New
York: Cambridge University Press; 2009. p. 55–90.
21. Purroy F, Montaner J, Molina CA, et al. Patterns and predictors of early risk of
recurrence after transient ischemic attack with respect to etiologic subtypes.
Stroke 2007;38:3225–9.
22. Cucchiara B, Kasner S. In the clinic: transient ischemic attack. Ann Intern Med
2011;154:ITC11–5 [quiz: ITC1–16].
23. Prabhakaran S, Silver AJ, Warrior L, et al. Misdiagnosis of transient ischemic
attack in the emergency room. Cerebrovasc Dis 2008;26:630–5.
24. Kraaijeveld CL, Van Gijn J, Schouten HJ, et al. Interobserver agreement for the
diagnosis of transient ischemic attacks. Stroke 1984;15:723–5.
25. Tomasello F, Mariani F, Fieschi C, et al. Assessment of inter-observer differences
in the Italian multicenter study on reversible cerebral ischemia. Stroke 1982;13:
32–5.
26. Castle J, Mlynash M, Lee K, et al. Agreement regarding diagnosis of transient
ischemic attack fairly low among stroke-trained neurologists. Stroke 2010;41:
1367–70.
27. Levy DE. How transient are transient ischemic attacks? Neurology 1988;38:
674–7.
28. Landi G. Clinical diagnosis of transient ischaemic attacks. Lancet 1992;15:
402–5.
29. Schrock JW, Glasenapp M, Victor A, et al. Variables associated with discordance between emergency physician and neurologist diagnoses of transient
ischemic attacks in the emergency department. Ann Emerg Med 2012;59:
19–26.
30. Lyrer P, Engelter S. Antithrombotic drugs for carotid artery dissection. Cochrane
Database Syst Rev 2010;(10):CD000255.
Transient Ischemic Attack
31. Amort M, Fluri F, Schafer J, et al. Transient ischemic attack versus transient
ischemic attack mimics: frequency, clinical characteristics and outcome. Cerebrovasc Dis 2011;32:57–64.
32. Lewandowski C, Rao C, Silver B. Transient ischemic attack: definitions and clinical presentations. Ann Emerg Med 2008;52:S7–16.
33. Kerber K, Brown D, Lisabeth L, et al. Stroke among patients with dizziness,
vertigo, and imbalance in the emergency department: a population-based
study. Stroke 2006;37:2484–7.
34. Norrving B, Magnusson M, Holtås S. Isolated acute vertigo in the elderly; vestibular or vascular disease? Acta Neurol Scand 1995;91:43–8.
35. Pantoni L, Lamassa M, Inzitari D. Transient global amnesia: a review emphasizing pathogenic aspects. Acta Neurol Scand 2000;102:275–83.
36. Sedlaczek O, Hirsch J, Grips E, et al. Detection of delayed focal MR changes in the
lateral hippocampus in transient global amnesia. Neurology 2004;62:2165–70.
37. Moreau F, Jeerakathil T, Coutts SB, et al. Patients referred for TIA may still have
persisting neurological deficits. Can J Neurol Sci 2012;39:170–3.
38. Gottesman RF, Alt J, Wityk RJ, et al. Predicting abnormal coagulation in
ischemic stroke: reducing delay in rt-PA use. Neurology 2006;67:1665–7.
39. Shah KH, Edlow JA. Transient ischemic attack: a review for the emergency
physician. Ann Emerg Med 2004;43:592–604.
40. Elkins JS, Sidney S, Gress D, et al. Electrocardiographic findings predict shortterm cardiac morbidity after transient ischemic attack. Arch Neurol 2002;59:
1437–41.
41. Barthélémy JC, Feasson-Gerard S, Garnier P, et al. Automatic cardiac event
recorders reveal paroxysmal atrial fibrillation after unexplained strokes or transient ischemic attacks. Ann Noninvasive Electrocardiol 2003;8:194–9.
42. Bogousslavsky J, Hachinski V, Boughner D, et al. Cardiac and arterial lesions in
carotid transient ischemic attacks. Arch Neurol 1986;43:223–8.
43. Strandberg M, Marttila RJ, Helenius H, et al. Transoesophageal echocardiography in selecting patients for anticoagulation after ischaemic stroke or transient
ischaemic attack. J Neurol Neurosurg Psychiatry 2002;73:29–33.
44. Yahia A, Shaukat A, Kirmani J, et al. Treatable potential cardiac sources of embolism in patients with cerebral ischemic events: a selective transesophageal
echocardiographic study. South Med J 2004;97:1055–9.
45. Giles MF, Albers GW, Amarenco P, et al. Addition of brain infarction to the
ABCD2 score (ABCD2I): a collaborative analysis of unpublished data on 4574
patients. Stroke 2010;41:1907–13.
46. Merwick A, Albers GW, Amarenco P, et al. Addition of brain and carotid imaging to
the ABCD2 score to identify patients at early risk of stroke after transient ischaemic
attack: a multicentre observational study. Lancet Neurol 2010;9:1060–9.
47. Ovbiagele B, Kidwell CS, Saver JL. Epidemiological impact in the United
States of a tissue-based definition of transient ischemic attack. Stroke 2003;
34:919–24.
48. Totaro P, Toni D, Durastani L, et al. Diffusion-weighted MRI in patients with nondiagnostic CT in the post-acute phase of cerebral ischemia. Eur Neurol 2010;
63:94–100.
49. Perrone P, Candelise L, Scotti G, et al. CT evaluation in patients with transient
ischemic attack: correlation between clinical and angiographic findings. Eur
Neurol 1979;18:217–21.
50. Douglas V, Johnston C, Elkins J, et al. Head computed tomography findings predict
short-term stroke risk after transient ischemic attack. Stroke 2003;34:2894–8.
765
766
Siket & Edlow
51. Ay H, Arsava EM, Johnston SC, et al. Clinical- and imaging-based prediction of
stroke risk after transient ischemic attack: the CIP model. Stroke 2009;40:181–6.
52. Singer OC, Sitzer M, du Mesnil de Rochemont R, et al. Practical limitations of
acute stroke MRI due to patient-related problems. Neurology 2004;62:1848–9.
53. Ginde AA, Foianini A, Renner DM, et al. Availability and quality of computed
tomography and magnetic resonance imaging equipment in U.S. emergency
departments. Acad Emerg Med 2008;15:780–3.
54. Perry JJ, Mansour M, Sharma M, et al. National survey of Canadian neurologists
current practice for transient ischemic attack and the need for a clinical decision
rule. Stroke 2010;41:987–91.
55. Prabhakaran S, Chong JY, Sacco RL. Impact of abnormal diffusion-weighted
imaging results on short-term outcome following transient ischemic attack.
Arch Neurol 2007;64:1105–9.
56. Buskens E, Nederkoorn PJ, Buijs-van der Woulde T, et al. Imaging of carotid
arteries in symptomatic patients: cost-effectiveness of diagnostic strategies.
Radiology 2004;233:101–12.
57. Feldmann E, Wilterdink JL, Kosinski A, et al. The stroke outcomes and neuroimaging of intracranial atherosclerosis (SONIA) trial. Neurology 2007;68:
2099–106.
58. Meseguer E, Lavalle PC, Mazighi M, et al. Yield of systemic transcranial Doppler
in patients with transient ischemic attack. Ann Neurol 2010;68:9–17.
59. Wright VL, Olan W, Dick B, et al. Assessment of CE-MRA for the rapid detection
of supra-aortic vascular disease. Neurology 2005;65:27–32.
60. Josephson SA, Bryant SO, Mak HK, et al. Evaluation of carotid stenosis using
CT angiography in the initial evaluation. Neurology 2004;63:457–60.
61. Klingebiel R, Kentenich M, Bauknecht HC, et al. Comparative evaluation of 64slice CT angiography and digital subtraction angiography in assessing the cervicocranial vasculature. Vasc Health Risk Manag 2008;4:901–7.
62. Ois A, Gomis M, Rodriguez-Campello A, et al. Factors associated with a high
risk of recurrence in patients with transient ischemic attack or minor stroke.
Stroke 2008;39:1717–21.
63. Poisson SN, Nguyen-Huynh MN, Johnston SC, et al. Intracranial large vessel
occlusion as a predictor of decline in functional status after transient ischemic
attack. Stroke 2011;42:44–7.
64. Coutts SB, Modi J, Patel SK, et al. CT/CT angiography and MRI findings predict
recurrent stroke after transient ischemic attack and minor stroke: results of the
prospective CATCH study. Stroke 2012;43:1013–7.
65. Mnyusiwalla A, Aviv RI, Symons SP. Radiation dose from multidetector row CT
imaging for acute stroke. Neuroradiology 2009;51:635–40.
66. Mlynash M, Olivot JM, Tong DC, et al. Yield of combined perfusion and diffusion
MR imaging in hemispheric TIA. Neurology 2009;72:1127–33.
67. Restrepo L, Jacobs MA, Barker PB, et al. Assessment of transient ischemic
attack with diffusion- and perfusion-weighted imaging. Am J Neuroradiol
2004;25:1645–52.
68. Krol AL, Coutts SB, Simon JE, et al. Perfusion MRI abnormalities in speech or
motor transient ischemic attack patients. Stroke 2005;36:2487–9.
69. Perez A, Restrepo L, Kleinman JT, et al. Patients with diffusion-perfusion
mismatch on magnetic resonance imaging 48 hours or more after stroke
symptom onset: clinical and imaging features. J Neuroimaging 2006;16:329–33.
70. Prabhakaran S, Patel SK, Samuels J, et al. Perfusion computed tomography in
transient ischemic attack. Arch Neurol 2011;68:85–9.
Transient Ischemic Attack
71. Asdaghi N, Hameed B, Saini M, et al. Acute perfusion and diffusion abnormalities predict early new MRI lesions 1 week after minor stroke and transient
ischemic attack. Stroke 2011;42:2191–5.
72. Olivot JM, Albers GW. Diffusion-perfusion MRI for triaging transient ischemic
attack and acute cerebrovascular syndromes. Curr Opin Neurol 2011;24:44–9.
73. Kernan WN, Horwitz RI, Brass LM, et al. A prognostic system for transient
ischemia or minor stroke. Ann Intern Med 1991;114:552–7.
74. Hankey GJ, Slattery JM, Warlow CP. Transient ischaemic attacks: which patients
are at high (and low) risk of serious vascular events? J Neurol Neurosurg Psychiatr 1992;55:640–52.
75. Rothwell PM, Giles MF, Flossman E, et al. A simple score (ABCD) to identify individuals at high early risk of stroke after transient ischaemic attack. Lancet 2005;
366:29–36.
76. 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.
77. Purroy F, Molina CA, Montaner J, et al. Absence of usefulness of ABCD score in
the early risk of stroke of transient ischemic attack patients. Stroke 2007;38:
855–6 [author reply: 857].
78. Amarenco P, Labreuche J, Lavallee PC, et al. Does ABCD2 score below 4 allow
more time to evaluate patients with a transient ischemic attack? Stroke 2009;40:
3091–5.
79. Asimos AW, Johnson AM, Rosamond WD, et al. A multicenter evaluation of the
ABCD2 score’s accuracy for predicting early ischemic stroke in admitted
patients with transient ischemic attack. Ann Emerg Med 2010;55:201–10.
80. Chandratheva A, Geraghty OC, Luengo-Fernandez R, et al. ABCD 2 score
predicts severity rather than risk of early. Stroke 2010;41:851–6.
81. Sheehan OC, Merwick A, Kelly LA, et al. Diagnostic usefulness of the ABCD2
score to distinguish transient ischemic attack and minor ischemic stroke from
noncerebrovascular events: the North Dublin TIA study. Stroke 2009;40:3449–54.
82. Giles MF, Rothwell PM. Systematic review and pooled analysis of published and
unpublished validations of the ABCD and ABCD2 transient ischemic attack risk
scores. Stroke 2010;41:667–73.
83. Yang J, Fu JH, Chen XY, et al. Validation of the ABCD 2 score to identify the
patients with high risk of late stroke after a transient ischemic attack or minor
ischemic stroke. Stroke 2010;41:1298–300.
84. Tsivgoulis G, Heliopoulos I. Potential and failure of the ABCD2 score in stroke
risk prediction after transient ischemic attack. Stroke 2010;41:836–8.
85. Sanders LM, Srikanth VK, Blacker DJ, et al. Clinical prediction with the ABCD2
score: at what cost? Stroke 2010;41:e589 [author reply: e590].
86. Giles MF, Albers GW, Amarenco P, et al. Early stroke risk and ABCD2 score
performance in tissue- vs time-defined TIA: a multicenter study. Neurology
2011;13:1222–8.
87. Ong ME, Chan YH, Lin WP, et al. Validating the ABCD(2) score for predicting stroke
risk after transient ischemic attack in the ED. Am J Emerg Med 2010;28:44–8.
88. Cancelli I, Janes F, Gigli GJ. Incidence of transient ischemic attack and early
stroke risk: validation of the ABCD2 score in an Italian population-based study.
Stroke 2011;42:2751–7.
89. Perry JJ, Sharma M, Sivilotti ML, et al. Prospective validation of the ABCD2
score for patients in the emergency department with transient ischemic attack.
CMAJ 2011;183:1137–45.
767
768
Siket & Edlow
90. Edlow JA. Stroke: TIA-is ABCD2 useful in choosing who, what, where and when?
Nat Rev Neurol 2011;7:542–4.
91. Asimos AW, Rosamond WD, Johnson AM, et al. Early diffusion weighted MRI as
a negative predictor for disabling stroke after ABCD2 score risk categorization
in transient ischemic attack patients. Stroke 2009;40:3252–7.
92. Sorensen AG, Ay H. Transient ischemic attack: definition, diagnosis, and risk
stratification. Neuroimaging Clin N Am 2011;21:303–13.
93. Engelter ST, Amort M, Jax F, et al. Optimizing the risk estimation after a transient
ischaemic attack - the ABCDE1 score. Eur J Neurol 2012;19:55–61.
94. Goldstein LB, Jones MR, Matchar DB, et al. Improving the reliability of stroke
subgroup classification using the trial of ORG 10172 in acute stroke treatment
(TOAST) criteria editorial comment: classifying the mechanisms of ischemic
stroke. Stroke 2001;32:1091–7.
95. Ay H, Furie KL, Singhal A, et al. An evidence-based causative classification
system for acute ischemic stroke. Ann Neurol 2005;58:688–97.
96. Ay H, Benner T, Arsava EM, et al. A computerized algorithm for etiologic classification of ischemic stroke: the Causative Classification of Stroke System. Stroke
2007;38:2979–84.
97. Ay H, Gungor L, Arsava EM, et al. A score to predict early risk of recurrence
after ischemic stroke. Neurology 2010;74:128–35.
98. 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;42:2186–90.
99. National Institute for Health and Clinical Excellence. NICE clinical guideline 68, july
23, 2008. Stroke: diagnosis and initial management of acute stroke and transient
ischaemic attack (TIA). Available at: www.nice.org.uk/nicemedia/live/12018/
41331/41331.pdf. Accessed June 25th, 2012.
100. Wojner-Alexander AW, Garami Z, Chernyshev OY, et al. Heads down: flat positioning improves blood flow velocity in acute ischemic stroke. Neurology 2005;
64:1354–7.
101. Singhal AB, Benner T, Roccatagliata L, et al. A pilot study of normobaric oxygen
therapy in acute ischemic stroke. Stroke 2005;36:797–802.
102. Morten O, Guldvog B. Should stroke victims routinely receive supplemental
oxygen?: a quasi-randomized controlled-trial. Stroke 1999;30:2033–7.
103. Adams HP, del Zoppo G, Alberts MJ, et al. Guidelines for the early management
of adults with ischemic stroke. Stroke 2007;38:1655–711.
104. Oliveira-Filho J, Silva SCS, Trabuco CC, et al. Detrimental effect of blood pressure
reduction in the first 24 hours of acute stroke onset. Neurology 2003;61:1047–51.
105. Ahmed N, Wahlgren NG. Effects of blood pressure lowering in the acute phase
of total anterior circulation infarcts and other stroke subtypes. Cerebrovasc Dis
2003;15:235–43.
106. Lavallée PC, Meseguer E, Abboud H, et al. A transient ischaemic attack clinic
with round-the-clock access (SOS-TIA): feasibility and effects. Lancet Neurol
2007;6:953–60.
107. Luengo-Fernandez R, Gray AM, Rothwell PM. Effect of urgent treatment for transient ischaemic attack and minor stroke on disability and hospital costs (EXPRESS study):
a prospective population-based sequential comparison. Lancet Neurol 2009;8:235–43.
108. Furie KL, Kasner SE, Adams RJ, et al. AHA/ASA guidelines for the prevention of
stroke in patients with stroke or transient ischemic attack. A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:1–50.
Transient Ischemic Attack
109. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised
trials of antiplatelet therapy for prevention of death, myocardial infarction, and
stroke in high risk patients. BMJ 2002;324:71–86.
110. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole
versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238–51.
111. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared
with clopidogrel alone after recent ischaemic stroke or transient ischaemic
attack in high-risk patients (MATCH): randomised, double-blind, placebocontrolled trial. Lancet 2004;364:331–7.
112. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone
for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706–17.
113. Kennedy J, Hil MD, Ryckborst KJ, et al. Fast assessment of stroke and transient
ischaemic attack to prevent early recurrence (FASTER): a randomised
controlled pilot trial. Lancet Neurol 2007;6:961–9.
114. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in
patients with atrial fibrillation. N Engl J Med 2009;361:1139–51.
115. Rothwell PM, Eliasziw M, Gutnikov SA, et al. Endarterectomy for symptomatic
carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet
2004;363:915–24.
116. Amarenco P, Bogousslavsky J, Callahan A, et al. High-dose atorvastatin after
stroke or transient ischemic attack. N Engl J Med 2006;355:549–59.
117. Lee CD, Folsom AR, Blair SN. Physical activity and stroke risk: a meta-analysis.
Stroke 2003;34:2475–81.
118. Ross M, Nahab F. Management of transient ischemia attacks in the twenty-first
century. Emerg Med Clin North Am 2009;27:51–69.
119. Amarenco P, Labreuche J, Lavallée PC. Patients with transient ischemic attack
with ABCD2 <4 can have similar 90-day stroke risk as patients with transient
ischemic attack with ABCD2 >54. Stroke 2012;43:863–5.
120. Al-Khaled M, Matthis C, Eggers J. Short-term risk and predictors of stroke after
transient ischemic attack. J Neurol Sci 2012;312:79–81.
121. Nguyen-Huynh MN, Johnston SC. Is hospitalization after TIA cost-effective on
the basis of treatment with tPA? Neurology 2005;65:1799–801.
122. Joshi JK, Ouyang B, Prabhakaran S. Should TIA patients be hospitalized or
referred to a same-day clinic?: a decision analysis. Neurology 2011;77:2082–8.
123. von Weitzel-Mudersbach P, Johnsen SP, Andersen G. Low risk of vascular
events following urgent treatment of transient ischaemic attack: the Aarhus
TIA study. Eur J Neurol 2011;18:1285–90.
124. Olivot J-M, Wolford C, Castle J, et al. Two aces: transient ischemic attack work-up as
outpatient assessment of clinical evaluation and safety. Stroke 2011;42:1839–43.
125. Stead LG, Bellolio MF, Suravaram S, et al. Evaluation of transient ischemic attack
in an emergency department observation unit. Neurocrit Care 2009;10:204–8.
126. Ross MA, Compton S, Medado P, et al. An emergency department diagnostic
protocol for patients with transient ischemic attack: a randomized controlled
trial. Ann Emerg Med 2007;50:109–19.
127. Nahab F, Leach G, Kingston C, et al. Impact of an emergency department
observation unit transient ischemic attack protocol on length of stay and cost.
J Stroke Cerebrovasc Dis 2011. [Epub ahead of print].
128. Torres Macho J, Peña Lillo G, Pérez Martı́nez D, et al. Outcomes of atherothrombotic transient ischemic attack and minor stroke in an emergency
department: results of an outpatient management program. Ann Emerg Med
2011;57:510–6.
769
770
Siket & Edlow
129. Rothwell PM, Giles MF, Chandratheva A, et al. Effect of urgent treatment of transient ischaemic attack and minor stroke on early recurrent stroke (EXPRESS
study): a prospective population-based sequential comparison. Lancet 2007;
370:1432–42.
130. Whiteley W, Tseng MC, Sandercock P. Blood biomarkers in the diagnosis of
ischemic stroke: a systematic review. Stroke 2008;39:2902–9.
131. Corso G, Bottacchi E, Brusa A, et al. Blood C-reactive protein concentration with
ABCD2 is a better prognostic tool than ABCD2 alone. Cerebrovasc Dis 2011;32:
97–105.
132. Katan M, Nigro N, Flurl F, et al. Stress hormones predict cerebrovascular
re-events after transient ischemic attacks. Neurology 2011;76:563–6.
133. Cucchiara BL, Messe SR, Sansing L, et al. Lipoprotein-associated phospholipase A2 and C-reactive protein for risk-stratification of patients with TIA. Stroke
2009;40:2332–6.
134. Montaner J, Perea-Gainza M, Delgado P, et al. Etiologic diagnosis of ischemic
stroke subtypes with plasma biomarkers. Stroke 2008;39:2280–7.
135. Zhan X, Jickling GC, Tian Y, et al. Transient ischemic attacks characterized by
RNA profiles in blood. Neurology 2011;77:1718–24.
136. Montaner J, Mendioroz M, Ribo M, et al. A panel of biomarkers including
caspase-3 and D-dimer may differentiate acute stroke from stroke-mimicking
conditions in the emergency department. J Intern Med 2011;270:166–74.