Professional Documents
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2020 TIA Clinical Practice
2020 TIA Clinical Practice
Clinical Practice
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence sup-
porting various strategies is then presented, followed by a review of formal guidelines, when they exist. The
article ends with the author’s clinical recommendations.
A 54-year-old man presents 2 hours after sudden weakness in his left arm prevented
him from turning the steering wheel while driving. His symptoms lasted for 30 min-
utes. He has hypertension and hyperlipidemia, for which he takes an angiotensin-
receptor blocker and a statin, and he is a smoker with a 30 pack-year history. On ex-
amination, the blood pressure is 156/96 mm Hg. How should this patient be further
evaluated and treated?
A
pproximately 20 to 25% of ischemic strokes are heralded by From the Department of Neurology and
transient ischemic symptoms1 (Table 1). These symptoms usually last for Stroke Center, Assistance Publique–
Hôpitaux de Paris, SOS-TIA Clinic, Bichat
seconds or minutes and typically last less than 1 hour.2 An older, time- Hospital, Laboratory for Vascular Trans-
based definition of transient ischemic attack (TIA) (based on symptoms lasting lational Science, INSERM Unité 1148,
<24 hours) has been revised owing to the identification of an infarct on brain Département Hospitalo Universitaire–
Fibrose Inflammation Remodelage, Uni-
imaging in many patients with symptoms that last more than 10 minutes and versity of Paris, Paris. Address reprint
given that many patients who arrive at the hospital within 6 hours after the onset requests to Dr. Amarenco at the Depart-
of symptoms are considered for urgent revascularization. The new definition of ment of Neurology and Stroke Center,
Bichat Hospital, 46 rue Henri Huchard,
TIA is now “tissue-based.” An ischemic lesion is not visible on brain imaging in a Paris 75018, France, or at pierre.amarenco@
patient with TIA,3-5 and a patient with transient symptoms who has even a tiny aphp.fr.
ischemic brain lesion on imaging is considered to have had a minor ischemic N Engl J Med 2020;382:1933-41.
stroke.3-5 Since TIA and minor ischemic stroke generally have the same clinical DOI: 10.1056/NEJMcp1908837
manifestations (except for neuroimaging findings) and management, they are Copyright © 2020 Massachusetts Medical Society.
Definite TIA
Focal cerebral or retinal symptoms lasting for seconds or minutes and typically lasting <1 hr
Motor weakness in two limbs or in one limb and the face
Sensory deficit in two limbs or in one limb and the face
Visual-field defect (homonymous hemianopia) or monocular blindness
Aphasia or dysarthria
Possible TIA†
Unsteady gait
Diplopia
Vertigo, dizziness
Dysphagia
Usually not a TIA‡
Amnesia
Confusion
Incoordination of limbs
Partial sensory deficit (abnormal sensation or deficit in one limb or only in the face)
Unusual cortical visual symptoms (lone bilateral blindness and bilateral positive visual phenomena)§
Transient loss of consciousness
Headache
Phosphenes, photopsias, complex visual hallucinations, and palinopsia
A B C
monitoring of the cardiac rhythm, and laboratory Figure 2 (facing page). Diagnosis, Evaluation, and Treatment
testing as clinically indicated (e.g., measurement of Transient Ischemic Attack and Minor Ischemic Stroke.
of the C-reactive protein level and erythrocyte The score on the ABCD2 scale is calculated on the basis
sedimentation rate in patients with findings of age, blood pressure, the presence of clinical weakness
such as headache or transient monocular blind- or speech disturbance, the duration of symptoms, and
ness that are suggestive of giant-cell arteritis) the presence or absence of diabetes. “Bizarre spells”
are nonfocal or not clearly focal transient neurologic
(Fig. 2; and Table S1 in the Supplementary Ap- events for which the type of onset, topography, and
pendix, available with the full text of this article course of symptoms do not fulfill the criteria for definite
at NEJM.org). or possible TIA or another definite or possible neuro-
In patients in whom the origin of the TIA is logic syndrome such as epilepsy or migraine. Fazekas
unclear after initial brain imaging and ECG, scores range from 0 (no leukoariosis) to III (confluent
leukoariosis). After the first-line evaluation, a second-
further evaluation may include prolonged cardiac line evaluation can be performed on an outpatient basis
monitoring (Holter monitoring or the use of an and may include more precise vascular imaging (e.g.,
implantable cardiac monitoring device).4 Con- high-resolution magnetic resonance imaging [MRI] of
trast transthoracic and transesophageal echocar- the cerebral artery, catheter-guided angiography of cere-
diography to detect cardiac structural abnor- bral arteries, tests to detect arteritis, or lumbar punc-
ture), further cardiac tests (e.g., 3-week Holter electro-
malities such as patent foramen ovale, atrial cardiography [ECG], the use of an implantable cardiac
thrombus, and valvular disease or atherosclero- monitoring device, or transesophageal echocardiogra-
sis of the aortic arch as a source of cerebral phy), and tests to determine rare causes of the symp-
embolism24-26 may be performed if these find- toms (e.g., alpha-galactosidase A deficiency, JAK2 mu-
ings will alter management.4 Other tests may be tation, and antiphospholipid antibodies). To convert
values for low-density lipoprotein (LDL) cholesterol to
performed in selected cases (e.g., to detect a millimoles per liter, multiply by 0.02586. CRP denotes
JAK2 mutation in a patient with suspected poly- C-reactive protein, CT computed tomography, CTA CT
cythemia vera). angiography, DWI diffusion-weighted imaging, ECAS
Treatment to prevent a recurrent, potentially extracranial carotid-artery stenosis, ESR erythrocyte
more severe ischemic event is the main initial sedimentation rate, FLAIR fluid-attenuated inversion
recovery, GRE gradient echo, ICAO internal carotid-
goal and is guided by an assessment of the risk artery origin, ICAS intracranial carotid-artery stenosis,
of such an event on the basis of the initial evalu- LVEF left ventricular ejection fraction, MRA magnetic
ation. The score on the ABCD2 scale (calculated resonance angiography, SVD small-vessel disease, SWI
on the basis of age, blood pressure, the presence susceptibility-weighted imaging, TEE transesophageal
of clinical weakness or speech disturbance, the echocardiography, and TTE transthoracic echocardi
ography.
duration of symptoms, and the presence or
absence of diabetes) is used to predict the risk
of stroke. ABCD2 scores range from 0 to 7, with The ABCD2 score was previously recommend-
higher scores indicating a greater risk of stroke ed for use in triage. For example, previous Na-
(Table S2).27 The ABCD2-I score is a refined score tional Institute for Health and Care Excellence
that also includes findings on diffusion-weighted (NICE) guidelines called for immediate hospital-
imaging of the brain. This score has been shown ization of patients with an ABCD 2 score of 4 or
to improve risk prediction over the ABCD2 score higher but allowed up to 8 days for evaluation in
alone.28 In one study, among 3206 patients in patients with scores lower than 4, provided that
whom TIA or minor ischemic stroke was evalu- aspirin was immediately initiated.6 However,
ated with the use of an ABCD2 score and imag- subsequent data have called this strategy into
ing, the 7-day risk of stroke was 7.1%, as com- question. In some studies involving large co-
pared with 0.4% among those who had positive horts of patients presenting with TIA, serious
findings on diffusion-weighted imaging.29 The findings on evaluation (e.g., clinically signifi-
addition of carotid-artery stenosis of at least 50% cant extracranial-artery stenosis, intracranial-
or “dual” TIA (TIA prompting medical attention artery stenosis, or atrial fibrillation) were de-
plus at least one TIA in the preceding 7 days) tected in 20% of those with an ABCD2 score
also improved the performance of the ABCD3-I lower than 4, and the 3-month risk of stroke
score.30 among these patients was similar to that among
Diagnosis of TIA
Patient has had transient neurologic
symptoms with no persisting deficit
DWI is positive: brain infarction or TIA mimics: migraine attack, bizarre spells,
infarctions, indicated by bright white DWI is normal: TIA epileptic seizure, benign positional
spot or spots paroxysmal vertigo, transient global
Possible diagnosis of minor ischemic stroke amnesia, anxiety, or panic attack
First-Line Evaluation
Findings
ICAO stenosis >50% → consider Atrial fibrillation → oral anticoagulation Definite SVD
endarterectomy, stenting, or both (consider other major cardiac source One or several small deep infarcts
ICAS or ECAS <50% of embolism, such as mitral stenosis, Confluent leukoaraiosis (Fazekas III)
No atherosclerosis left ventricular thrombosis, endocarditis, ≥3 Microbleeds
Neck or cerebral-artery dissection or LVEF <35%) Enlarged perivascular spaces
Moderate or minor cardiac source of Possible SVD
embolism (e.g., LVEF ≥35%, isolated One isolated deep-brain infarct
patent foramen ovale, atrial septal Fully normal brain parenchyma
aneurysm, mitral-valve prolapse or strands) Mild leukoaraiosis (Fazekas I or II)
No cardiac disease <3 Microbleeds
Treatment
All discharged with best medical therapy
Clopidogrel (75 mg) plus aspirin (75 mg/day for the first 21 days) Blood pressure <140/90 mm Hg or <130/80 in patients with
followed by aspirin (75 mg) or clopidogrel (75 mg/day) to 90 days or diabetes and SVD; LDL cholesterol <70 mg/dl if atherosclerosis;
anticoagulation in case of major cardiac source of embolism glycated hemoglobin <7%
Smoking cessation; physical exercise; counseling regarding diet
patients with a score of 4 or higher.10,31,32 In one hemorrhage in the two trials, respectively.35-37
of these cohorts (in the TIAregistry.org project Post hoc analyses of these trials showed that the
study), the strongest predictors of a new vascular benefit of the combination treatment was seen
event were carotid stenosis, atrial fibrillation, during the first 21 days, without a significant
multiple ischemic spots on diffusion-weighted increase in major hemorrhage complications.37,38
imaging, and an ABCD2 score of 6 or 7.10 Hence, Previous trials have shown that anticoagulant
when a patient is evaluated urgently, the scoring treatment was not superior to aspirin in patients
system is not relevant, since treatment decisions with noncardioembolic TIA or stroke. If atrial
are based on etiologic findings. NICE guidelines fibrillation is detected after the TIA, oral anti-
that were updated in 2019 no longer recommend coagulant treatment should be initiated without
the clinical use of scoring systems such as delay.
ABCD 2 for triage,33 although scores remain use-
ful in research (e.g., for the selection of patients Treatment of Associated Risk Factors
at high risk in a randomized, controlled trial) In patients with TIA, long-term treatment in-
and in areas where urgent evaluation that in- volves blood pressure–lowering and lipid-lower-
cludes specialist input is not readily available, ing therapy4,39 and control of diabetes. Smoking
since no useful blood biomarker has been vali- cessation and lifestyle changes are also recom-
dated for TIA. mended. It is reasonable to target blood pressure
to less than 140/90 mm Hg; a target below
130/80 mm Hg is appropriate for patients with
T r e atmen t
lacunar stroke or diabetes5 and is appropriate
Antiplatelet Therapy more generally if the patient can achieve these
In patients with noncardioembolic ischemic levels without adverse effects. Randomized trials
stroke, aspirin is the most effective treatment to involving patients with recent ischemic stroke or
reduce the risk of recurrent stroke during the TIA have shown significant decreases in the risk
first 90 days, and it is the only antiplatelet treat- of stroke and overall cardiovascular events with
ment that has been shown to reduce the risk of high-dose statins39 or those specifically target-
recurrent disabling ischemic stroke (i.e., ische ing a low-density lipoprotein (LDL) cholesterol
mic stroke in patients with a score on the level of less than 70 mg per deciliter (1.8 mmol
modified Rankin scale of 2 or more (scores per liter).40 Thus, intensive statin therapy is rec-
range from 0 [no symptoms] to 6 [death]) during ommended when an atherosclerotic origin of the
that period.34 However, beyond 3 months, the TIA is presumed, regardless of the baseline LDL
efficacy of aspirin has been less clear.34 On the cholesterol level.5
basis of clinical trials that have shown effective- All patients should be screened and treated
ness, a loading dose of aspirin (300 mg orally) for diabetes mellitus and should receive counsel-
should be administered as soon as possible after ing regarding lifestyle (e.g., diet, weight loss,
TIA symptoms,5 before admission or on arrival smoking cessation, and the importance of three
for urgent care. The patient should be encour- to four exercise sessions per week).5 Screening
aged to take aspirin immediately at home if pos- for sleep apnea is also recommended.5
sible.34 Aspirin should then be continued at a Carotid endarterectomy or stenting should be
dose of 75 to 100 mg per day for 90 days.5 considered in patients in whom the underlying
Two trials have shown that dual antiplatelet cause of TIA is ipsilateral internal-carotid-artery
treatment (a loading dose of 300 mg of clopido- stenosis of 50% or more.5 Stenting of intracra-
grel plus 300 mg of aspirin, followed by a main- nial stenosis is not usually recommended.5
tenance dose of 75 mg of clopidogrel and 75 mg
of aspirin during the first 21 or 90 days after TIA Evaluation
TIA or minor ischemic stroke) reduced the risk TIA can be a challenging diagnosis even for ex-
of stroke by 25%, as compared with aspirin perienced vascular neurologists, and careful and
alone. There was a 3.5-percentage-point and rapid evaluation is needed even for atypical symp-
1.5-percentage-point absolute reduction in the toms, given the potentially catastrophic risks of
risk of stroke and a 0-percentage-point and a missed diagnosis.7,11,41,42 On the basis of obser-
0.5-percentage-point absolute excess of major vational data showing associated decreases in
the 3-month risk of stroke and length of stay platelet therapy of aspirin and clopidogrel for 21
and cost, as well as improved patient satisfac- days is considered by many experts to be the
tion,11,12,43 TIA clinics with round-the-clock eval- standard of care,44 yet clopidogrel is less effec-
uation have been promoted and developed as an tive or not effective in patients who are carriers
addition to many comprehensive stroke centers, of CYP2C19 loss-of-function alleles (as many as
particularly in Europe, Australia, and Cana- 20 to 40% of the population, depending on eth-
da.6,15,33,42 Alternatively, urgent evaluation can be nic group),45 and screening for clopidogrel resis-
performed in emergency departments where tance has not been validated for clinical use.
stroke expertise and imaging are readily available. Ongoing randomized trials involving patients
with previous TIA or stroke are assessing the
benefits and risks of ticagrelor, an alternative,
A r e a s of Uncer ta in t y
directly-acting antiplatelet agent that does not
Without findings on neuroimaging, the diagno- need to be metabolized, in combination with as-
sis of TIA is often uncertain, particularly in pa- pirin, as compared with aspirin alone (Clinical-
tients with isolated, “bizarre,” or nonfocal symp- Trials.gov number, NCT03354429), triple anti-
toms (Table 1). (“Bizarre spells” or isolated atypical thrombotic strategies (a dual antiplatelet agent plus
symptoms are nonfocal or not clearly focal a short-term oral anticoagulant) (NCT03766581),
transient neurologic events for which the type of and an intravenous tissue plasminogen activator
onset, topography, and course of symptoms do in patients with intracranial large-vessel occlu-
not fulfill the criteria for definite or possible TIA sion (NCT02398656). Randomized trials have
or another definite or possible neurologic syn- shown a benefit of antiinflammatory agents in
drome such as epilepsy or migraine.) Research is decreasing the incidence of cardiovascular events
needed to identify blood biomarkers or new among patients with previous myocardial infarc-
neuroimaging techniques that might improve tion46,47; colchicine is currently under study in pa-
the diagnosis. tients who have had a TIA or stroke (NCT02898610).
TIA and minor ischemic stroke are both char- There is uncertainty as to whether, beyond 90
acterized by the absence of disability (score on days, lifelong treatment with aspirin is useful in
the modified Rankin scale, 0 or 1). Many ische low-risk patients with TIA (i.e., those in whom
mic events that were previously considered to be brain-tissue damage has not been detected on
TIAs (according to the time-based definition) diffusion-weighted imaging, with no document-
are now considered to be “minor strokes” on the ed stenosis in the ipsilateral cerebral artery, no
basis of the presence of a bright spot or spots on major cardiac source of embolism, no small-
diffusion-weighted imaging (Fig. 1). This defini- vessel disease, and an ABCD2 score of <4). Simi-
tion may complicate interpretation of the results larly, investigation is needed of the benefit of
of clinical trials in which stroke outcomes in- aspirin beyond 90 days relative to bleeding risk
clude these events along with major strokes that among patients with isolated diplopia, amnesia,
cause disability. visual defect, vertigo, dizziness or gait instability,
A meta-analysis of individual patient data34 dysarthria, or isolated aphasia or weakness in the
from trials of antiplatelet therapy for secondary leg, arm, or both lasting less than 10 minutes.
prevention of TIA and minor ischemic stroke Aggressive lowering of LDL cholesterol levels
showed a considerable early benefit (in the first (e.g., to <55 mg per deciliter [1.4 mmol per liter])
2 weeks) of aspirin (93% relative reduction in the has been shown to reduce cardiovascular risks
risk of early recurrent stroke). This finding sup- after the acute coronary syndrome and ischemic
ports a benefit of a loading dose (300 mg) of stroke.40,48-50 Studies to determine the role of this
oral aspirin as soon as possible after the first strategy in patients with TIA are warranted.
TIA symptoms occur. If possible, patients should The length of hospitalization for low-risk pa-
take aspirin before they seek clinical care34 tients (e.g., those with an ABCD2 score of <4) is
(Fig. 2), but this strategy has not been formally uncertain. Whether these patients should be ad-
evaluated. mitted for evaluation and treatment for less than
Randomized trials are needed to determine 1 day, as reported by the SOS-TIA researchers,11 or
the best antithrombotic strategy for patients whether longer hospitalization for in-hospital
with TIA (or minor ischemic stroke). Dual anti- cardiac monitoring is required is unclear.
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