Stroke Etiology: Diagnostic Evaluation & Prevention

REVIEW ARTICLE

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
Diagnostic Evaluation of
Stroke Etiology
By James F. Meschia, MD, FAAN
ABSTRACT
OBJECTIVE: Precise therapies require precise diagnoses. This article provides
an evidence-based approach to confirming the diagnosis of ischemic
stroke, characterizing comorbidities that provide insights into the
pathophysiologic mechanisms of stroke, and identifying targets for
treatment to optimize the prevention of recurrent stroke.
LATEST DEVELOPMENTS: Identifying the presence of patent foramen ovale,
intermittent atrial fibrillation, and unstable plaque is now routinely
included in an increasingly nuanced workup in patients with stroke, even as
ongoing trials seek to clarify the best approaches for treating these and
other comorbidities. Multicenter trials have demonstrated the therapeutic
utility of patent foramen ovale closure in select patients younger than age
60 years. Insertable cardiac monitors detect atrial fibrillation lasting more
than 30 seconds in about one in ten patients monitored for 12 months
following a stroke. MRI of carotid plaque can detect unstable plaque at
risk of being a source of cerebral embolism.
ESSENTIAL POINTS: To optimize the prevention of recurrent stroke, it is
CITE AS:
CONTINUUM (MINNEAP MINN)
2023;29(2, CEREBROVASCULAR
DISEASE):412–424.
Address correspondence to
Dr James F. Meschia, Division of
Cerebrovascular Disease,
Department of Neurology, Mayo
Clinic, Jacksonville, FL 32224,
[email protected].
RELATIONSHIP DISCLOSURE:
The institution of Dr Meschia has
received research support from
the National Institute of
Neurological Disorders and
Stroke.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Meschia reports no
disclosure.
© 2023 American Academy
of Neurology.
important to consider pathologies of intracranial and extracranial blood
vessels and of cardiac structure and rhythm as well as other inherited or
systemic causes of stroke. Some aspects of the stroke workup should be
done routinely, while other components will depend on the clinical
circumstances and preliminary testing results.
INTRODUCTION
ith the advent of evidence-based mechanical thrombectomy, it
is tempting to view all ischemic strokes as falling into two
broad categories: strokes caused by an accessible clot (large
vessel occlusion) and everything else. This perspective, while
pragmatic when presented in the emergency department with
a patient with acute stroke, is woefully inadequate when attempting to optimize
prevention of recurrent stroke. To optimize prevention, a more nuanced
characterization of stroke is required. While trying to identify stroke etiology is
customary, usually etiology can only be inferred through identifying, or not
identifying, various comorbidities. Often we cannot be certain that a specific
comorbidity truly was on the causal pathway to the presenting stroke, in part
because multiple comorbidities frequently coexist in the same patient. For some
comorbidities, such as carotid atherosclerotic stenosis, whether a specific
W
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treatment (eg, endarterectomy) is indicated depends on whether the
comorbidity is believed to be mechanistically related to stroke by perfusion zone
(eg, symptomatic versus asymptomatic stenosis). For other comorbidities,
such as atrial fibrillation, the indicated treatment is influenced by the increased
risk associated with a history of stroke. For example, stroke increases the
CHA2DS2-VASc risk estimation score (consisting of congestive heart failure,
hypertension, age 75 years or older, diabetes mellitus, previous stroke, vascular
disease, age 65 to 74 years, and sex category) by two points.1 Reference to a
“stroke workup” (ie, a set of diagnostic tests performed because a patient has had
a recent stroke) can be found in the medical literature since at least the early
1980s.2 The stroke workup has advanced in parallel with progress in diagnostic
technologies and medical and interventional therapies. While some elements of
the stroke workup should be done routinely in nearly all cases, other elements are
contingent on clinical circumstances. Recently, the American Heart Association/
American Stroke Association (AHA/ASA) published evidence-based guidelines
on stroke prevention in patients with recent stroke or transient ischemic attack
(TIA).3 These guidelines have a section on the diagnostic evaluation of patients
that includes an algorithm for ordering diagnostic tests annotated with class of
recommendation and level of evidence for each decision (FIGURE 1-1). This article
explains the AHA/ASA guidelines, puts them in clinical context, and highlights
recent substantial advances. Hemorrhagic stroke will be addressed only insofar as
it can mimic ischemic stroke at presentation.
CLINICAL ASSESSMENT
Before launching into a diagnostic workup, a focused but detailed clinical
assessment of the patient experiencing stroke should be performed.4 The history
of the present illness will include stroke symptoms and time last known to be at
neurologic baseline. Patients should be questioned about recent prior transient
neurologic deficits consistent with TIAs. Often these events will not be
volunteered spontaneously because the patient is overwhelmed with concern
over their presenting symptoms. If multiple TIAs have occurred, the physician
should determine whether they all conform to dysfunction in the same area of
perfusion (eg, left anterior circulation), which would suggest upstream
atherosclerotic stenosis, and how many attacks occurred within 2 weeks of
presentation (three or more attacks suggests unstable plaque).5 The physician
should ask about head or neck trauma or high-velocity chiropractic neck
manipulation, as these may cause arterial dissection.6 The physician should also
inquire about the use of drugs that can precipitate stroke such as amphetamines
and cocaine.7 Although understudied, routine use of cannabis appears to
significantly increase risk of stroke.8 Head or neck external beam radiotherapy
should also be queried, as this can cause a vasculopathy. Vascular risk factors
need to be surveyed, including the status of atrial fibrillation and all the
components of CHA2DS2-VASc. A history of migraine should also be discussed,
as migraine can be a stroke mimic or chameleon9 as well as a risk factor or cause
of stroke.10 Migraine with or without aura is also an important component of the
cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL) phenotype. Head, neck, and chest pain can
point to various stroke-relevant conditions, such as cervicocephalic arterial
dissection, aortic dissection, or myocardial infarction.11 A family history of
dementia, migraines, venous thrombosis, and premature atherosclerosis, not
KEY POINTS
● The stroke workup is the
set of diagnostic tests
performed to gain insight
into modifiable risk factors
and stroke mechanism. The
stroke workup has fixed and
variable components, the
latter being contingent on
clinical circumstances,
initial testing, and
therapeutic objectives.
● Recent American Heart
Association guidelines on
secondary stroke
prevention include an
algorithm for performing an
evidence-based diagnostic
evaluation.
● Three or more transient
ischemic attacks in a 2-week
period in the same arterial
distribution suggest an
unstable atherosclerotic
plaque as a mechanism.
● A stroke evaluation
should include examining
the patient for preceding
strokes or transient ischemic
attacks, atherosclerotic risk
factors, head or neck trauma
or radiation therapy,
migraines, and a family
history of stroke or
dementia.
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DIAGNOSTIC EVALUATION OF STROKE ETIOLOGY
FIGURE 1-1
Algorithm for evaluating patients with a clinical diagnosis of stroke to optimize prevention of
recurrent stroke.
CT = computed tomography; CTA = computed tomography angiography; ECG = electrocardiography;
MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; SOE = source of embolism;
TEE = transesophageal echocardiography.
a
When a patient has a transient neurologic deficit clinically characteristic of transient ischemic attack, the
patient should be evaluated in the same manner as a patient who has an ischemic stroke with a
corresponding cerebral infarct on imaging.
b
Basic laboratory tests include complete blood count, troponin, prothrombin time, partial thromboplastin
time, glucose, hemoglobin A1c, creatinine, and fasting or nonfasting lipid profile.
Reprinted with permission from Kleindorfer DO, et al, Stroke.3
merely stroke, must be obtained to properly assess potential heritable risk
factors.
Cursory screening examinations miss strokes. Emergency medical services
miss about one-fourth of strokes using screening examinations like FAST (facial
drooping, arm weakness, speech difficulties, and time of onset).12 The most
common symptoms among false-negative stroke cases are speech disturbance,
nausea and vomiting, dizziness, changes in mental status, and visual complaints.
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Every patient should have a National Institutes of Health Stroke Scale (NIHSS)
assessment performed by a certified examiner. The acute NIHSS score, which
is an excellent predictor of outcomes, also moderately correlates with acute
diffusion-weighted imaging (DWI) and perfusion-weighted imaging lesion
volumes.13 However, an NIHSS score of 0 does not mean that the patient has not
had a stroke. Nearly 5% of strokes, most of which are lacunar and infratentorial,
will score a 0 on the NIHSS.14 These 0-point strokes are not benign and have
similar stroke recurrence rates as other stroke types. All potential acute stroke
patients deserve a thorough neurologic examination; however, given the time
constraints of decision making in the emergency department, a thorough
neurologic examination may not be appropriate at the time. Nonetheless, after
performing an NIHSS assessment, if uncertainty about whether the patient had a
stroke remains, a few quick bedside tests can enhance the NIHSS examination to
bring out focal deficits often poorly characterized or missed entirely by the scale.
Dysarthria testing in the NIHSS is not very sensitive. The patient can be asked to
repeat “PA-TA-KA” three or four times to elicit scanning dysarthria or other
impairment in forming labial, lingual, or fricative sounds. The physician can also
perform “H” testing for external ophthalmoparesis and test for clumsy hands or
distal weakness by having the patient tap the thumb and index finger as fast as
possible (test each side separately to avoid mirror movements) and look for
left-right asymmetry.
Head CT, CT angiography, and, where appropriate, CT perfusion should be
obtained as soon as possible to provide information about vessel occlusion,
infarct core, ischemic penumbra, and degrees of collaterals (the so-called
“imaging is brain” paradigm).15 Because of this time pressure, performing a
thorough neurovascular clinical assessment prior to imaging is neither realistic
nor even appropriate, but after the go/no-go decisions to proceed with
thrombolysis or mechanical thrombectomy have been made, one should return
to the patient’s bedside and explore the clinical case in greater detail.
KEY POINTS
● Nearly 5% of strokes,
most of which are lacunar
and infratentorial, have a
National Institutes of Health
Stroke Scale (NIHSS) score
of 0. Although these strokes
are usually not treated with
thrombolytics, they are
nonetheless important to
recognize because the
stroke recurrence rates for
NIHSS 0 and non-0 strokes
are very similar.
● Nearly 7% of acute
ischemic strokes do not
have a focal area of
restricted diffusion on initial
diffusion-weighted imaging.
Patients with posterior
circulation stroke are 5 times
as likely to have diffusionweighted imaging–negative
stroke as patients with
anterior circulation stroke.
BRAIN IMAGING
The first diagnostic step after clinical assessment is to determine with CT or MRI
of the head whether a patient who presents with signs and symptoms of an acute
stroke has had an acute ischemic stroke (AHA/ASA class 1 recommendation).3
National guidelines recommend initial imaging within 25 minutes of arrival
at a stroke center to screen patients for thrombolysis with or without
thrombectomy.16 Patients routinely receive a head CT combined with CT
angiography, with or without CT perfusion, to rule out intracranial hemorrhage
and assess for large vessel occlusion and ischemic penumbra. In many instances,
this imaging is sufficient to confirm the diagnosis of acute ischemic stroke,
although small strokes are often missed. If the patient remains symptomatic and
multimodal CT imaging does not confirm the diagnosis, then MRI with DWI will
often suffice. DWI is so sensitive and specific for acute cerebral infarcts, even for
punctate lesions of only a few millimeters, that it is sometimes forgotten that a
negative scan does not completely rule out a stroke (CASE 1-1). Nearly 7% of
patients with acute ischemic stroke will have DWI-negative stroke.17 Patients
with posterior circulation stroke are 5 times as likely to have DWI-negative stroke
as patients with anterior circulation stroke.17
A head CT can reasonably be avoided in favor of MRI in neurologically stable
patients who present late or with minor, nondisabling deficits. For patients who
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DIAGNOSTIC EVALUATION OF STROKE ETIOLOGY
present late, the brain MRI should include DWI sequences. In a consecutive
series of 300 patients presenting 3 or more days after TIA or minor stroke, DWI
showed a high-signal lesion in 70% of cases of stroke and 13% of cases of TIA and
provided clinically meaningful information (eg, confirming the diagnosis or
vascular territory of the lesion) in 36% of cases.18 Patients with minor (NIHSS
score ≤3), nondisabling (modified Rankin scale, 0 or 1) stroke do not clearly
benefit from thrombolytic therapy and rarely have a large vessel occlusion that
requires immediate thrombectomy, so the timeliness of multimodal CT can be
traded for the diagnostic yield of MRI. The diagnostic yield of DWI falls with
lower NIHSS scores17 but remains clinically meaningful, even for patients with
resolved deficits (TIAs).19 MRI with DWI can detect acute ischemic stroke in
about 20% of patients presenting with acute dizziness and vertigo, whereas the
sensitivity of CT for diagnosing acute ischemic stroke (typically posterior
inferior cerebellar artery infarcts) in this patient population is under 10%.20
CASE 1-1
A 93-year-old man with hypertension presented to the emergency
department with sudden generalized weakness, which had begun the
previous day. The morning of presentation he could barely get out of bed
and fell while trying to get to the bathroom. His son had to help him get
off the floor. He did not hit his head, and the patient denied trouble with
balance, vision, facial droop, speech, or language. On repeated
questioning, he endorsed that his weakness may have been worse on his
left side. He denied prior strokes, other neurologic illnesses, cancer,
fevers, chills, shortness of breath, angina pectoris, or recent change in
medications. He was taking lisinopril and hydrochlorothiazide. His
temperature was 36.6°C (97.8°F), and his blood pressure was
162/95 mm Hg. His general physical examination was unremarkable. His
National Institutes of Health Stroke Scale score was 6 (his left arm had
some effort against gravity; right arm and both legs drifted; and there was
ataxia on left-sided finger-to-nose testing). Complete blood count, basic
metabolic panel, and thyroid-stimulating hormone (TSH) were normal,
and chest x-ray showed clear lungs. Urinalysis showed no signs of
infection. Head CT showed no acute intracranial abnormality. Brain MRI
revealed an acute subcortical infarction in the right paracentral lobule
and old small infarcts in the right frontal corona radiata and right
thalamus as well as extensive small vessel ischemic disease seen on
T2 fluid-attenuated inversion recovery (FLAIR). (FIGURE 1-2) CT angiography
revealed highly calcified stenosis (<50%) of the right internal carotid
artery. Transthoracic echocardiogram detected concentric left
ventricular hypertrophy and a left ventricular ejection fraction of 71%.
In-patient cardiac monitoring showed no atrial fibrillation.
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Patients with nonlacunar stroke can present with a classic lacunar syndrome:
ataxic hemiparesis, dysarthria–clumsy hand syndrome, pure hemiparesis, pure
hemisensory loss, or sensorimotor stroke. Almost one in six patients presenting
with a classic lacunar syndrome has multiple infarctions demonstrated on DWI.21
MRI is usually required to detect acute infarcts in multiple cerebral circulations.
This pattern of lesions can be found in about 10% of patients with acute
infarction and is attributable to cardioembolism half of the time and less
frequently to a hematologic or vasculitic mechanism.22
CERVICOCEPHALIC ARTERIAL IMAGING
The AHA/ASA regards noninvasive imaging by ultrasonography, CT
angiography, or magnetic resonance angiography (MRA) of the cervical anterior
circulation (both carotid arteries) as a class 1 recommendation in patients with
symptomatic infarction in the zone perfused by the anterior circulation.3 The
FIGURE 1-2
Imaging of the patient in CASE 1-1. Axial diffusion-weighted (A) and T2 fluid-attenuated
inversion recovery (FLAIR) (B) sequences of brain MRI showing an acute ischemic stroke
and severe cerebral small-vessel ischemic disease. If the patient’s MRI had been delayed
it might have been impossible to appreciate that there had been an acute focal area of
ischemia given the preexisting severe white matter ischemic changes.
This patient presented with vague symptoms of generalized weakness, but
the abrupt onset and slight asymmetry to the motor examination favored
diagnosis of an acute stroke. The head CT was only helpful in excluding an
intraparenchymal or subdural hemorrhage that could present similarly.
Although suspicion was high for an acute ischemic stroke after the CT, the
brain MRI was helpful in securing a positive diagnosis. Knowing the size and
location of the acute infarct and the presence of comorbid small vessel
disease also helps with prognostication and planning of rehabilitation.
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COMMENT
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CASE 1-2
A 75-year-old right-handed man noted the sudden onset of numbness and
clumsiness in his left hand. He chose to go to bed and see if his symptoms
would pass; when they did not, he presented for medical attention at the
emergency department. He had a history of hyperlipidemia, but no prior
neurologic history. He quit cigarette smoking more than two decades
prior. He denied chest pain or palpitations. Vital signs were unremarkable.
His National Institutes of Health Stroke Scale score was 7 (aphasia and
left-sided numbness and weakness). Initial head CT showed an old right
frontal infarction, but no acute changes. CT angiography showed no large
vessel occlusion but did show an estimated 50% to 70% stenosis of the
cervical right internal carotid artery. The next day a brain MRI showed
scattered infarcts in the right frontal parietal lobes on DWI and a right
frontal gliotic infarct on T2 fluid-attenuated inversion recovery (FLAIR). MR
angiography estimated the right internal carotid artery stenosis to be 50%.
MR plaque imaging (FIGURE 1-3) showed hemorrhagic plaque with a lipid core
in the right carotid bifurcation extending 18 mm into the internal carotid
artery. The patient was referred for revascularization.
FIGURE 1-3
Imaging of the patient in CASE 1-2. Two-dimensional spin echo T1-weighted double inversion
recovery images in two consecutive axial sections (A, B) of the neck at the C3 to C4 levels of
the cervical spine show hemorrhagic plaque in the right internal carotid artery. Arrows
indicate hyperintensities in the carotid plaque corresponding to plaque hemorrhage. MRI
can be protocoled to highlight several features of plaque composition that indicate a
so-called unstable or vulnerable plaque. There is an increased risk of stroke recurrence in
the territory of brain supplied by an artery with vulnerable plaque.
COMMENT
This patient presented outside of a time window to allow for safe
thrombolysis and did not have a large vessel occlusion to treat with
mechanical thrombectomy. However, MRI was useful in ensuring that his
stroke involved the right anterior circulation. CT angiography and MR
angiography supported a moderate-to-severe carotid stenosis of the right
internal carotid artery. Plaque characteristics were those seen in so-called
vulnerable or unstable plaque and represented high-risk features. Most
studies support early revascularization (within 2 weeks, and preferably
within 2 days).
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AHA/ASA regards noninvasive imaging using CT angiography or MRA of the
posterior circulation (vertebrobasilar arteries) and intracranial arteries as a
class 2a recommendation.3 The difference in recommendation level can be
explained by the proven effectiveness of revascularization of a highly stenotic
symptomatic cervical carotid artery, whereas there is no compelling evidence for
angioplasty, stenting, or surgery of symptomatic vertebrobasilar or intracranial
arteries. The distinction between imaging anterior versus posterior and
intracranial arteries is moot for most patients as those with suspected ischemic
stroke are now routinely submitted to emergent CT angiography of head and
neck to screen for large vessel occlusion warranting attempted mechanical
thrombectomy. CT angiography is particularly good for detecting carotid webs,
which appear as a thin intraluminal filling defect along the posterior wall of the
carotid bulb just distal to the bifurcation on oblique sections and as a septum on
axial sections.23 If protocoled appropriately, vessel-wall imaging using MRI
technology can identify several features associated with plaque vulnerability:
intraplaque hemorrhage, a lipid-rich necrotic core, and thinning of the fibrous
cap (CASE 1-2).24
KEY POINTS
● CT angiography in the
oblique and axial planes is
the imaging modality of
choice for identifying
carotid webs.
● Long-term cardiac
rhythm monitoring detects
severalfold more cases of
atrial fibrillation than routine
inpatient monitoring
following a stroke (12.1%
versus 1.8%), although the
minimum burden of
intermittent atrial fibrillation
to justify anticoagulation
remains uncertain.
CARDIAC RHYTHM ASSESSMENT
Every patient with stroke should have an ECG to screen for atrial fibrillation or
flutter and, even if there is a well-documented history of atrial fibrillation, to
screen for cardiac comorbidities like acute or chronic myocardial infarction and
left ventricular hypertrophy (AHA/ASA class 1 recommendation).3 Long-term
rhythm monitoring is an AHA/ASA class 2a recommendation for patients with
cryptogenic stroke and no contraindication to anticoagulation.3 This monitoring
can be done in various ways, including mobile cardiac outpatient telemetry or an
insertable loop recorder. The longer the rhythm is monitored the more likely
atrial fibrillation is to be detected. For example, in the STROKE-AF (Rate of
Atrial Fibrillation Through 12 Months in Patients With Recent Ischemic Stroke
of Presumed Known Origin) trial, 12 months of insertable cardiac monitoring
detected severalfold more cases of atrial fibrillation than routine care in patients
with recent ischemic stroke (12.1% versus 1.8%).25 Currently, oral anticoagulation
is an AHA/ASA class 1 (level of evidence B-R) recommendation for atrial
fibrillation, whether paroxysmal, persistent, or permanent.3 However, uncertainty
remains around the optimal duration of monitoring and the minimum burden
of atrial fibrillation detection necessary to justify long-term oral anticoagulation.
As noted in a recent editorial,26 trials have shown that many patients have
subclinical atrial fibrillation after non–atrial-fibrillation-related ischemic stroke;
the longer the monitoring, the more subclinical atrial fibrillation will be detected.
Furthermore, there appears to be a dose relationship between duration of
atrial fibrillation and stroke risk.27 Future trials are underway to clarify the
threshold of subclinical atrial fibrillation that justifies long-term anticoagulation.
STRUCTURAL CARDIAC IMAGING
Echocardiography with or without contrast is an AHA/ASA class 2a
recommendation for patients with cryptogenic stroke. Transesophageal
echocardiography (TEE), cardiac CT, or cardiac MRI of patients with embolic
stroke of undetermined significance is an AHA/ASA class 2b recommendation.3
Echocardiography can detect a host of pathologies that predispose a patient to
cardioembolism; some are common, such as patent foramen ovale, and many are
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DIAGNOSTIC EVALUATION OF STROKE ETIOLOGY
rare, such as atrial myxoma, papillary fibroelastoma, and valvular vegetations.
Many echocardiographically detected abnormalities are likely etiologically
related but are not likely to change management. For example, patients with
known atrial fibrillation and a moderate to high CHA2DS2-VASc score need
long-term oral anticoagulation regardless of whether a thrombus is identified by
echocardiography in the left atrium, left atrial appendage, or aorta. TEE is
generally considered more sensitive and specific than transthoracic
echocardiogram (TTE) for detecting sources of cardioembolism, but the
discovery of pathologies that should alter management occurs in less than 5% of
cases.28 TEE, the more invasive test, may be less effective in detecting patent
foramen ovale than TTE with contrast and the Valsalva maneuver.29
EMBOLIC STROKE OF UNDETERMINED SOURCE
Embolic stroke of undetermined source (ESUS) is a diagnostic subset of ischemic
stroke. ESUS is a diagnosis made by negation (ie, that the stroke is not lacunar in
size and is not associated with large vessel high-grade stenosis or obvious cardiac
source of embolism).30 ESUS is a subset of cryptogenic stroke. A stroke may be
cryptogenic because a cursory workup failed to identify an etiology. However,
ESUS requires a certain diagnostic intensity, with a proposed workup including
brain imaging, ECG, transthoracic echocardiography, cardiac monitoring for at
least 24 hours, and imaging of both intracranial and extracranial arteries.30 Only
when and if clinical trials clearly establish that patients with ESUS require
treatment different from patients without ESUS will the concept truly be
proven useful.
TESTING FOR INHERITED STROKE SYNDROMES
Testing for single-gene disorders that cause stroke is of vanishingly low yield in
most stroke patients and should not be done routinely. However, certain clinical
scenarios should push the neurologist to perform targeted testing. This author
has found the yield to be much higher when patients have a positive family
history or a plethora of recurrent strokes and a paucity of conventional risk
factors, particularly if the strokes appear to be related to small vessel disease
(<15-mm infarcts with unremarkable MRA or CT angiography). There are
many well-characterized monogenic cerebral small vessel diseases: CADASIL;
cerebral autosomal recessive arteriopathy with subcortical infarcts and
leukoencephalopathy (CARASIL); pontine autosomal dominant microangiopathy
and leukoencephalopathy (PADMAL); Fabry disease; mitochondrial
encephalopathy, lactic acidosis, and strokelike episodes (MELAS); and type IV
collagen–related diseases (COL4A1/COL4A2 mutations).31,32 At present, none
of these conditions are curable, but that should not dissuade the neurologist
from securing a definitive diagnosis with gene testing. A definitive diagnosis can
avoid mistreatment for conditions that the patient does not have (eg, multiple
sclerosis or central nervous system [CNS] vasculitis). Family history taking
has evolved in the postgenomic era; some patients may present as at-risk because
they were contacted by a relative about the results of a direct-to-consumer
genomic test that found a mutation in NOTCH3. Ultimately, if a patient is
diagnosed with a monogenic stroke syndrome, the physician should refer the
patient to genetic counseling to properly review who may or may not be at risk in a
family and what the medical, occupational, and social implications are for
presymptomatic testing.
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HEMATOLOGIC DISORDERS AND HYPERCOAGULABLE STATES
It is vital to diagnose sickle cell disease or be aware of the diagnosis in patients
who present with stroke because proven, highly effective therapies exist,
including hydroxycarbamide, blood transfusions, and hematopoietic stem cell
transplantation.33 Sickle cell disease causes ischemic stroke, hemorrhagic stroke,
and moyamoya vasculopathy. In children and adolescents, transcranial Doppler
screening for elevated blood flow velocities in the middle cerebral artery can
detect signs of an emerging vasculopathy for which exchange transfusions
dramatically reduce the risk of stroke.
Indiscriminate screening for thrombophilia is low yield in patients with
ischemic stroke. Testing patterns vary greatly, and testing results in a treatment
change only about 1% to 8% of the time.34 Among young patients with ischemic
stroke, rates of positive thrombophilia screening are higher but management
changes in only 8% of patients.35 Screening for hypercoagulable states like
protein C, protein S, and antithrombin III deficiencies, and factor V Leiden
and prothrombin 20210 mutations seems justifiable in patients with cerebral
venous thrombosis.36
Antiphospholipid antibody syndrome is an acquired hypercoagulable state
in which the main manifestations are recurrent thromboses (thrombotic
antiphospholipid syndrome) and pregnancy complications (obstetric
antiphospholipid syndrome). Current diagnostic criteria require persistently
(12 or more weeks) positive lupus anticoagulant, anti–β2 glycoprotein I, or
anticardiolipin antibodies.37 Routine screening for antiphospholipid antibodies
is hard to justify. APASS (Antiphospholipid Antibody and Stroke Study)
was a prospective, observational study nested within a multicenter randomized
trial of warfarin versus aspirin for the prevention of stroke recurrence.
This study of more than 1700 patients did not find the presence of
antiphospholipid antibodies to predict increased stroke risk or a differential
response to treatment.38 Diagnostic nihilism is not appropriate either. Some
patients can have a severe variant of the syndrome known as catastrophic
antiphospholipid syndrome, a life-threatening syndrome requiring immediate
treatment.39
INFECTIOUS CAUSES OF STROKE
Being vigilant for an infectious etiology is crucial, not because it is common, but
because delay in diagnosis can have devastating consequences. Embolism from
infective endocarditis occurs in less than 2% of all patients hospitalized with
stroke.40 Both native and prosthetic valves can become infected. Although
transcatheter aortic valve replacement generally has lower overall risk than open
surgical aortic valve replacement, the risk of subsequent endocarditis appears
to be comparable with both valve procedures.41 In an administrative data review
of nonfederal acute care hospitals in California, the absolute increase in risk of
stroke was 9.1% in the month after diagnosis of infectious endocarditis.42
Interestingly, the risk of stroke was significantly elevated in the 4 months preceding
the diagnosis of infectious endocarditis. While this increased risk might be the result
of a systemic inflammatory state, some of the increase might be due to delayed
diagnosis of infective endocarditis. Suspicion for infective endocarditis should be
raised if C-reactive protein levels are higher than 10 mg/L.40 In most patients with
known or suspected infective endocarditis, acute ischemic lesions and cerebral
microbleeds are seen on brain MRI, with other hemorrhagic lesions seen in about
KEY POINTS
● Transesophageal
echocardiography may be
less sensitive in detecting
patent foramen ovale than
contrasted transthoracic
echocardiography.
● To diagnose embolic
stroke of undetermined
source, patients should have
a stroke workup that
includes, at a minimum,
brain imaging, ECG,
transthoracic
echocardiography, cardiac
monitoring for at least
24 hours, and imaging of
both intracranial and
extracranial arteries.
● The yield of testing for
genetic stroke syndromes is
much higher when patients
have a positive family history
or a plethora of recurrent
strokes and a paucity of
conventional risk factors,
particularly if the strokes are
due to small vessel disease.
● Patients with aseptic
cerebral venous thrombosis
should be screened for
thrombophilia.
● A C-reactive protein level
higher than 10 mg/L should
raise suspicion for stroke
caused by endocarditis.
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DIAGNOSTIC EVALUATION OF STROKE ETIOLOGY
one-fourth of patients and intracranial mycotic aneurysms occurring in less than
10% of patients.43 DWI may help differentiate acute cardioembolism from infective
endocarditis from nonbacterial thrombotic endocarditis. One large, single-center
study found that all patients (14/14) with nonbacterial thrombotic endocarditis
had numerous <10 mm, 10 mm to 30 mm, and >30 mm lesions in multiple
territories, whereas patients with infective endocarditis showed different patterns,
including having a single lesion, a territorial infarction, or disseminated punctate
lesions.44 When clinical suspicion for infective endocarditis is high, it may be
necessary to repeat echocardiography, optimally TEE, to secure a diagnosis.45
In addition to infections causing endocarditis and, secondarily,
cardioembolism, infections can cause stroke through cerebral vasculitis.46 The
microbiological differential diagnosis is quite different; common conditions and
organisms associated with infectious cerebral vasculitis include syphilis, Lyme
disease, invasive fungi, and herpes zoster. Headache, seizures, and
encephalopathy are commonly associated with stroke due to infectious cerebral
vasculitis. Diagnosis of an infectious cerebral vasculitis typically requires
angiography (CT angiography, MRA, or digital-subtraction catheter angiography)
as well as appropriate microbiological studies of blood and CSF. Sometimes brain
biopsy is required.
AUTOINFLAMMATORY CENTRAL NERVOUS SYSTEM VASCULITIS
Stroke is rarely caused by noninfectious vasculitis, so vigilance is required for
early diagnosis. Several rheumatologic conditions can cause CNS vasculitis:
giant cell arteritis, Takayasu disease, eosinophilic granulomatosis with
polyangiitis, granulomatosis with polyangiitis, polyarteritis nodosa, and
Buerger disease. Clues found during the neurologic evaluation that lead to
the diagnosis of an underlying systemic vasculitis causing CNS vasculitis
include mononeuritis multiplex, visual loss, seizures, muscle disease, and
encephalopathy.47 Primary CNS vasculitis is particularly challenging to
diagnose. Suspicion for the condition may be raised in an individual who is
40 to 60 years old who has headache, encephalopathy, and ischemic or
hemorrhagic strokes. A normal brain MRI practically excludes the diagnosis, while
an abnormal CSF is seen in 80% to 90% of affected individuals.48 Brain biopsy
is the only way of securing a definitive premortem diagnosis, but sensitivity is
poor. If the cerebral angiogram is consistent with CNS vasculitis, there may be
reluctance to pursue a tissue diagnosis. However, brain biopsy may identify a
lymphoproliferative disease or an infectious vasculitis in more than 30% of cases.49
CONCLUSION
The stroke workup has evolved and expanded with advances in diagnostic
testing and refinement in clinical trials of stroke prevention. Some tests are
fundamental to nearly every patient, while others should be performed only in
response to positive or negative results of first-round testing or in the context
of specific clinical situations (eg, strongly positive family history of stroke).
Because the stroke evaluation has fixed and variable elements, the workup
may be at risk of cognitive biases like anchoring, premature closure, and
availability of testing.50 It is important to revisit presumptions of etiology,
particularly when patients have recurrent stroke despite good medical
compliance.
422
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