Diagnostic Evaluation of Stroke Etiology 2023

REVIEW ARTICLE
Diagnostic Evaluation of
Stroke Etiology

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
3WZuNYbiUxL+Qx0CJDbgM62RHmPuolEo5N+/X7zoAmdaTwqB+KcSbKRp5behT+Ql0Mk3bty1xhQyZS7k1ah5dNhzzpFEIa7vzF7r
ONLINE
By James F. Meschia, MD, FAAN
Downloaded from http://journals.lww.com/continuum by 1dc+NBdzNCtjMFW413F/U85CIXLyZuC9qekkv+z4kRVCS54
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.
Qc4vxUDBJnwzf on 04/11/2023
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)
important to consider pathologies of intracranial and extracranial blood
2023;29(2, CEREBROVASCULAR vessels and of cardiac structure and rhythm as well as other inherited or
DISEASE):412–424. systemic causes of stroke. Some aspects of the stroke workup should be
done routinely, while other components will depend on the clinical
Address correspondence to
Dr James F. Meschia, Division of circumstances and preliminary testing results.
Cerebrovascular Disease,
Department of Neurology, Mayo
Clinic, Jacksonville, FL 32224,
meschia.james@mayo.edu.
INTRODUCTION
W
RELATIONSHIP DISCLOSURE: ith the advent of evidence-based mechanical thrombectomy, it
The institution of Dr Meschia has is tempting to view all ischemic strokes as falling into two
received research support from
the National Institute of
broad categories: strokes caused by an accessible clot (large
Neurological Disorders and vessel occlusion) and everything else. This perspective, while
Stroke. pragmatic when presented in the emergency department with
UNLABELED USE OF a patient with acute stroke, is woefully inadequate when attempting to optimize
PRODUCTS/INVESTIGATIONAL prevention of recurrent stroke. To optimize prevention, a more nuanced
USE DISCLOSURE:
characterization of stroke is required. While trying to identify stroke etiology is
Dr Meschia reports no
disclosure. 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
© 2023 American Academy because multiple comorbidities frequently coexist in the same patient. For some
of Neurology. comorbidities, such as carotid atherosclerotic stenosis, whether a specific
412 APRIL 2023
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

treatment (eg, endarterectomy) is indicated depends on whether the KEY POINTS
comorbidity is believed to be mechanistically related to stroke by perfusion zone
● The stroke workup is the
(eg, symptomatic versus asymptomatic stenosis). For other comorbidities, set of diagnostic tests
such as atrial fibrillation, the indicated treatment is influenced by the increased performed to gain insight
risk associated with a history of stroke. For example, stroke increases the into modifiable risk factors
CHA2DS2-VASc risk estimation score (consisting of congestive heart failure, and stroke mechanism. The
stroke workup has fixed and
hypertension, age 75 years or older, diabetes mellitus, previous stroke, vascular

variable components, the
disease, age 65 to 74 years, and sex category) by two points.1 Reference to a latter being contingent on
“stroke workup” (ie, a set of diagnostic tests performed because a patient has had clinical circumstances,
a recent stroke) can be found in the medical literature since at least the early initial testing, and
therapeutic objectives.
1980s.2 The stroke workup has advanced in parallel with progress in diagnostic
technologies and medical and interventional therapies. While some elements of ● Recent American Heart
the stroke workup should be done routinely in nearly all cases, other elements are Association guidelines on
contingent on clinical circumstances. Recently, the American Heart Association/ secondary stroke
American Stroke Association (AHA/ASA) published evidence-based guidelines prevention include an
algorithm for performing an
on stroke prevention in patients with recent stroke or transient ischemic attack evidence-based diagnostic
(TIA).3 These guidelines have a section on the diagnostic evaluation of patients evaluation.
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 ● Three or more transient
ischemic attacks in a 2-week
explains the AHA/ASA guidelines, puts them in clinical context, and highlights
period in the same arterial
recent substantial advances. Hemorrhagic stroke will be addressed only insofar as distribution suggest an
it can mimic ischemic stroke at presentation. unstable atherosclerotic
plaque as a mechanism.
CLINICAL ASSESSMENT
● A stroke evaluation
Before launching into a diagnostic workup, a focused but detailed clinical should include examining
assessment of the patient experiencing stroke should be performed.4 The history the patient for preceding
of the present illness will include stroke symptoms and time last known to be at strokes or transient ischemic
neurologic baseline. Patients should be questioned about recent prior transient attacks, atherosclerotic risk
factors, head or neck trauma
neurologic deficits consistent with TIAs. Often these events will not be or radiation therapy,
volunteered spontaneously because the patient is overwhelmed with concern migraines, and a family
over their presenting symptoms. If multiple TIAs have occurred, the physician history of stroke or
should determine whether they all conform to dysfunction in the same area of dementia.
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
CONTINUUMJOURNAL.COM 413

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.
414 APRIL 2023

Every patient should have a National Institutes of Health Stroke Scale (NIHSS) KEY POINTS
assessment performed by a certified examiner. The acute NIHSS score, which
● Nearly 5% of strokes,
is an excellent predictor of outcomes, also moderately correlates with acute most of which are lacunar
diffusion-weighted imaging (DWI) and perfusion-weighted imaging lesion and infratentorial, have a
volumes.13 However, an NIHSS score of 0 does not mean that the patient has not National Institutes of Health
had a stroke. Nearly 5% of strokes, most of which are lacunar and infratentorial, Stroke Scale (NIHSS) score
of 0. Although these strokes
will score a 0 on the NIHSS.14 These 0-point strokes are not benign and have
are usually not treated with

similar stroke recurrence rates as other stroke types. All potential acute stroke thrombolytics, they are
patients deserve a thorough neurologic examination; however, given the time nonetheless important to
constraints of decision making in the emergency department, a thorough recognize because the
stroke recurrence rates for
neurologic examination may not be appropriate at the time. Nonetheless, after
NIHSS 0 and non-0 strokes
performing an NIHSS assessment, if uncertainty about whether the patient had a are very similar.
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. ● Nearly 7% of acute
Dysarthria testing in the NIHSS is not very sensitive. The patient can be asked to ischemic strokes do not
have a focal area of
repeat “PA-TA-KA” three or four times to elicit scanning dysarthria or other restricted diffusion on initial
impairment in forming labial, lingual, or fricative sounds. The physician can also diffusion-weighted imaging.
perform “H” testing for external ophthalmoparesis and test for clumsy hands or Patients with posterior
distal weakness by having the patient tap the thumb and index finger as fast as circulation stroke are 5 times
as likely to have diffusion-
possible (test each side separately to avoid mirror movements) and look for weighted imaging–negative
left-right asymmetry. stroke as patients with
Head CT, CT angiography, and, where appropriate, CT perfusion should be anterior circulation stroke.
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.
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

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.
416 APRIL 2023

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 COMMENT
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.

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).
418 APRIL 2023

AHA/ASA regards noninvasive imaging using CT angiography or MRA of the KEY POINTS
posterior circulation (vertebrobasilar arteries) and intracranial arteries as a
● CT angiography in the
class 2a recommendation.3 The difference in recommendation level can be oblique and axial planes is
explained by the proven effectiveness of revascularization of a highly stenotic the imaging modality of
symptomatic cervical carotid artery, whereas there is no compelling evidence for choice for identifying
angioplasty, stenting, or surgery of symptomatic vertebrobasilar or intracranial carotid webs.

arteries. The distinction between imaging anterior versus posterior and

● Long-term cardiac
intracranial arteries is moot for most patients as those with suspected ischemic rhythm monitoring detects
stroke are now routinely submitted to emergent CT angiography of head and severalfold more cases of
neck to screen for large vessel occlusion warranting attempted mechanical atrial fibrillation than routine
thrombectomy. CT angiography is particularly good for detecting carotid webs, inpatient monitoring
following a stroke (12.1%
which appear as a thin intraluminal filling defect along the posterior wall of the versus 1.8%), although the
carotid bulb just distal to the bifurcation on oblique sections and as a septum on minimum burden of
axial sections.23 If protocoled appropriately, vessel-wall imaging using MRI intermittent atrial fibrillation
technology can identify several features associated with plaque vulnerability: to justify anticoagulation
remains uncertain.
intraplaque hemorrhage, a lipid-rich necrotic core, and thinning of the fibrous
cap (CASE 1-2).24
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

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.
420 APRIL 2023

HEMATOLOGIC DISORDERS AND HYPERCOAGULABLE STATES KEY POINTS
It is vital to diagnose sickle cell disease or be aware of the diagnosis in patients
● Transesophageal
who present with stroke because proven, highly effective therapies exist, echocardiography may be
including hydroxycarbamide, blood transfusions, and hematopoietic stem cell less sensitive in detecting
transplantation.33 Sickle cell disease causes ischemic stroke, hemorrhagic stroke, patent foramen ovale than
and moyamoya vasculopathy. In children and adolescents, transcranial Doppler contrasted transthoracic
echocardiography.
screening for elevated blood flow velocities in the middle cerebral artery can
detect signs of an emerging vasculopathy for which exchange transfusions ● To diagnose embolic
dramatically reduce the risk of stroke. stroke of undetermined
Indiscriminate screening for thrombophilia is low yield in patients with source, patients should have
ischemic stroke. Testing patterns vary greatly, and testing results in a treatment a stroke workup that
includes, at a minimum,
change only about 1% to 8% of the time.34 Among young patients with ischemic brain imaging, ECG,
stroke, rates of positive thrombophilia screening are higher but management transthoracic
changes in only 8% of patients.35 Screening for hypercoagulable states like echocardiography, cardiac
protein C, protein S, and antithrombin III deficiencies, and factor V Leiden monitoring for at least
24 hours, and imaging of
and prothrombin 20210 mutations seems justifiable in patients with cerebral both intracranial and
venous thrombosis.36 extracranial arteries.

Antiphospholipid antibody syndrome is an acquired hypercoagulable state
in which the main manifestations are recurrent thromboses (thrombotic ● The yield of testing for
genetic stroke syndromes is
antiphospholipid syndrome) and pregnancy complications (obstetric
much higher when patients
antiphospholipid syndrome). Current diagnostic criteria require persistently have a positive family history
(12 or more weeks) positive lupus anticoagulant, anti–β2 glycoprotein I, or or a plethora of recurrent
anticardiolipin antibodies.37 Routine screening for antiphospholipid antibodies strokes and a paucity of
conventional risk factors,
is hard to justify. APASS (Antiphospholipid Antibody and Stroke Study)
particularly if the strokes are
was a prospective, observational study nested within a multicenter randomized due to small vessel disease.
trial of warfarin versus aspirin for the prevention of stroke recurrence.
This study of more than 1700 patients did not find the presence of ● Patients with aseptic
antiphospholipid antibodies to predict increased stroke risk or a differential cerebral venous thrombosis
should be screened for
response to treatment.38 Diagnostic nihilism is not appropriate either. Some thrombophilia.
patients can have a severe variant of the syndrome known as catastrophic
antiphospholipid syndrome, a life-threatening syndrome requiring immediate ● A C-reactive protein level
treatment.39 higher than 10 mg/L should
raise suspicion for stroke
caused by endocarditis.
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

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 APRIL 2023

REFERENCES
1 Lip GYH, Nieuwlaat R, Pisters R, et al. Refining 13 Fink JN, Selim MH, Kumar S, et al. Is the association
clinical risk stratification for predicting stroke of National Institutes of Health Stroke Scale scores
and thromboembolism in atrial fibrillation using a and acute magnetic resonance imaging stroke
novel risk factor-based approach: the euro heart volume equal for patients with right- and left-
survey on atrial fibrillation. Chest 2010;137(2): hemisphere ischemic stroke? Stroke 2002;33(4):
263-272. doi:10.1378/chest.09-1584 954-958. doi:10.1161/01.str.0000013069.24300.1d

2 Barber F, Rosen P, Okin T. Atrial myxoma 14 Eskioglou E, Huchmandzadeh Millotte M, Amiguet
presenting as stroke. Ann Emerg Med 1982;11(6): M, Michel P. National Institutes of Health Stroke
316-318. doi:10.1016/s0196-0644(82)80132-7 Scale zero strokes. Stroke 2018;49(12):3057-3059.
doi:10.1161/STROKEAHA.118.022517
3 Kleindorfer DO, Towfighi A, Chaturvedi S, et al.
2021 guideline for the prevention of stroke in 15 Puig J, Shankar J, Liebeskind D, et al. From “time is
patients with stroke and transient ischemic brain” to “imaging is brain”: a paradigm shift in
attack: a guideline from the American Heart the management of acute ischemic stroke. J
Association/American Stroke Association. Stroke Neuroimaging 2020;30(5):562-571. doi:10.1111/
2021;52(7):e364-e467. doi:10.1161/STR. jon.12693
0000000000000375
16 Kelly AG, Hellkamp AS, Olson D, et al. Stroke 2012;
4 Southerland AM. Clinical evaluation of the 43(5):1279-1284. doi:10.1161/STROKEAHA.111.626374
patient with acute stroke. Continuum (Minneap

Minn) 2017;23(1, Cerebrovascular Disease):40-61. 17 Edlow BL, Hurwitz S, Edlow JA. Diagnosis of
doi:10.1212/CON.0000000000000437 DWI-negative acute ischemic stroke: a
meta-analysis. Neurology 2017;89(3):256-262.
5 Fereydooni A, Gorecka J, Xu J, et al. Carotid doi:10.1212/WNL.0000000000004120
endarterectomy and carotid artery stenting for
patients with crescendo transient ischemic 18 Schulz UG, Briley D, Meagher T, et al. Diffusion-
attacks: a systematic review. JAMA Surg 2019; weighted MRI in 300 patients presenting late
154(11):1055-1063. doi:10.1001/jamasurg.2019.2952 with subacute transient ischemic attack or minor
stroke. Stroke 2004;35(11):2459-2465. doi:10.1161/
6 Biller J, Sacco RL, Albuquerque FC, et al. Cervical 01.STR.0000143455.55877.b9
arterial dissections and association with cervical
manipulative therapy: a statement for healthcare 19 Amarenco P. Transient ischemic attack. Reply. N
professionals from the American Heart Engl J Med 2020;383(16):-15961598. doi:10.1056/
Association/American Stroke Association. Stroke NEJMc2022610
2014;45(10):3155-3174. doi:10.1161/STR. 20 Kabra R, Robbie H, Connor SEJ. Diagnostic yield
0000000000000016 and impact of MRI for acute ischemic stroke in
7 Middlekauff HR, Cooper ZD, Strauss SB. Drugs of patients presenting with dizziness and vertigo.
misuse: focus on vascular dysfunction. Can J Clin Radiol 2015;70(7):736-742. doi:10.1016/j.
Cardiol 2022;38(9):1364-1377. doi: 10.1016/j. crad.2015.01.016
cjca.2022.04.011 21 Ay H, Oliveira-Filho J, Buonanno FS, et al. Diffusion-
8 Page RL, 2nd, Allen LA, Kloner RA, et al. Medical weighted imaging identifies a subset of lacunar
marijuana, recreational cannabis, and infarction associated with embolic source. Stroke
cardiovascular health: a scientific statement 1999;30(12):2644-2650. doi:10.1161/01.str.30.12.2644
from the American Heart Association. Circulation 22 Depuydt S, Sarov M, Vandendries C, et al.
2020;142(10):e131-e152. doi:10.1161/ Significance of acute multiple infarcts in multiple
CIR.0000000000000883 cerebral circulations on initial diffusion weighted
9 Otlivanchik O, Liberman AL. Migraine as a stroke imaging in stroke patients. J Neurol Sci 2014;
mimic and as a stroke chameleon. Curr Pain 337(1-2):151-155. doi:10.1016/j.jns.2013.11.039
Headache Rep 2019;23(9):63. doi:10.1007/ 23 Mac Grory B, Emmer BJ, Roosendaal SD, et al.
s11916-019-0801-1 Carotid web: an occult mechanism of embolic
10 Øie LR, Kurth T, Gulati S, et al. Migraine and risk of stroke. J Neurol Neurosurg Psychiatry 2020;91:
stroke. J Neurol Neurosurg Psychiatry 2020;91: 1283-1289. doi:10.1136/jnnp-2020-323938
593-604. doi:10.1136/jnnp-2018-318254 24 Saba L, Moody AR, Saam T, et al. Vessel
11 Cadena R. Cervical artery dissection: early wall-imaging biomarkers of carotid plaque
recognition and stroke prevention. Emerg vulnerability in stroke prevention trials: a
Med Pract 2016;18(7):1-24. viewpoint from the carotid imaging consensus
group. JACC Cardiovasc Imaging 2020;13(11):
12 Jones SP, Bray JE, Gibson JM, et al. 2445-2456. doi:10.1016/j.jcmg.2020.07.046
Characteristics of patients who had a stroke not
initially identified during emergency prehospital
assessment: a systematic review. Emerg Med J
2021;38(5):387-393. doi:10.1136/emermed-2020-
209607

25 Bernstein RA, Kamel H, Granger CB, et al. Effect 38 Levine SR, Brey RL, Tilley BC, et al.
of long-term continuous cardiac monitoring vs Antiphospholipid antibodies and subsequent
usual care on detection of atrial fibrillation in thrombo-occlusive events in patients with
patients with stroke attributed to large- or ischemic stroke. JAMA 2004;291(5):576-584.
small-vessel disease: the STROKE-AF doi:10.1001/jama.291.5.576
randomized clinical trial. JAMA 2021;325(21):
39 Carmi O, Berla M, Shoenfeld Y, Levy Y.
2169-2177. doi:10.1001/jama.2021.6470
Diagnosis and management of catastrophic

26 Tirschwell D, Akoum N. Detection of subclinical antiphospholipid syndrome. Expert Rev Hematol
atrial fibrillation after stroke: is there enough 2017;10(4):365-374. doi:10.1080/17474086.

evidence to treat? JAMA 2021;325(21):2157-2159. 2017.1300522
doi:10.1001/jama.2021.7429
40 Hobohm C, Hagendorff A, Schulz S, et al. Clinical
27 Noseworthy PA, et al. Subclinical and presentation and multi-parametric screening
device-detected atrial fibrillation: pondering the surrogates of ischemic stroke patients suffering
knowledge gap: a scientific statement from the from infective endocarditis. Cerebrovasc Dis
American Heart Association. Circulation 2019; 2016;41(1-2):60-67. doi:10.1159/000442005
140(25):e944-e963. doi:10.1161/CIR.
41 Goldsweig AM, Baron SJ. Prosthetic valve
0000000000000740
endocarditis: literally a growing concern
28 Shah S, Malik P, Patel U, et al. Diagnostic yield of following transcatheter aortic valve
TEE in patients with cryptogenic stroke and TIA replacement. Catheter Cardiovasc Interv 2022;
with normal TTE: a systematic review and 99(3):904-905. doi:10.1002/ccd.30126
meta-analysis. Neurol Int 2021;13(4):659-670.

42 Merkler AE, Chu SY, Lerario MP, et al. Temporal
doi:10.3390/neurolint13040063
relationship between infective endocarditis and
29 Rodrigues AC, Picard MH, Carbone A, et al. stroke. Neurology 2015;85(6):512-516. doi:10.1212/
Importance of adequately performed Valsalva WNL.0000000000001835
maneuver to detect patent foramen ovale during
43 Ahn Y, Joo L, Suh CH, et al. Impact of brain MRI on
transesophageal echocardiography. J Am Soc
the diagnosis of infective endocarditis and
Echocardiogr 2013;26(11):1337-1343. doi:10.1016/j.
treatment decisions: systematic review and
echo.2013.07.016
meta-analysis. AJR Am J Roentgenol 2022;218(6):
30 Hart RG, Diener HC, Connolly SJ. Embolic strokes 958-968. doi:10.2214/AJR.21.26896
of undetermined source: support for a new
44 Singhal AB, Topcuoglu MA, Buonanno FS. Acute
clinical construct–authors' reply. Lancet Neurol
ischemic stroke patterns in infective and
2014;13(10):967. doi:10.1016/S1474-4422(14)70197-8
nonbacterial thrombotic endocarditis: a
31 Mancuso M, Arnold M, Bersano A, et al. Monogenic diffusion-weighted magnetic resonance imaging
cerebral small-vessel diseases: diagnosis and study. Stroke 2002;33(5):1267-1273. doi:10.1161/
therapy. Consensus recommendations of the 01.str.0000015029.91577.36
European Academy of Neurology. Eur J Neurol
45 Baddour LM, Wilson WR, Bayer AS, et al. Infective
2020;27(6):909-927. doi:10.1111/ene.14183
endocarditis in adults: diagnosis, antimicrobial
32 Bersano A, Kraemer M, Burlina A, et al. Heritable therapy, and management of complications: a
and non-heritable uncommon causes of stroke. J scientific statement for healthcare professionals
Neurol 2021;268(8):2780-2807. doi:10.1007/ from the American Heart Association. Circulation
s00415-020-09836-x 2015;132(15):1435-1486. doi:10.1161/CIR.
0000000000000296
33 Kato GJ, Piel FB, Reid CD, et al. Sickle cell disease.
Nat Rev Dis Primers 2018;4:18010. doi:10.1038/ 46 Carod Artal FJ. Clinical management of infectious
nrdp.2018.10 cerebral vasculitides. Expert Rev Neurother 2016;
16(2):205-221. doi:10.1586/14737175.2015.1134321
34 May JE, Martin KD, Taylor LJ, et al. Current
practice and clinical utility of thrombophilia 47 Adams HP Jr. Cerebral vasculitis. Handb Clin
testing in hospitalized patients with acute Neurol 2014;119:475-494. doi:10.1016/B978-0-
ischemic stroke. J Stroke Cerebrovasc Dis 2020; 7020-4086-3.00031-X
29(11):105209. doi:10.1016/j.jstrokecerebrovasdis.
48 Salvarani C, Brown RD Jr, Hunder GG. Adult
2020.105209
primary central nervous system vasculitis. Lancet
35 Omran SS, Lerario MP, Gialdini G, et al. Clinical 2012;380(9843):767-777. doi:10.1016/S0140-
impact of thrombophilia screening in young 6736(12)60069-5
adults with ischemic stroke. J Stroke
49 Krawczyk M, Barra LJ, Sposato LA, Mandzia JL.
Cerebrovasc Dis 2019;28(4):882-889. doi:10.1016/
Primary CNS vasculitis: a systematic review on
j.jstrokecerebrovasdis.2018.12.006
clinical characteristics associated with abnormal
36 Green M, Styles T, Russell T, et al. Non-genetic biopsy and angiography. Autoimmun Rev 2021;
and genetic risk factors for adult cerebral venous 20(1):102714. doi:10.1016/j.autrev.2020.102714
thrombosis. Thromb Res 2018;169:15-22. doi:10.
50 Croskerry P. The rational diagnostician and
1016/j.thromres.2018.07.005
achieving diagnostic excellence. JAMA 2022;
37 Linnemann B. Antiphospholipid syndrome - an 327(4):317-318. doi:10.1001/jama.2021.24988
update. Vasa 2018;47(6):451-464. doi:10.1024/
0301-1526/a000723
424 APRIL 2023

Diagnostic Evaluation of Stroke Etiology 2023

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Diagnostic Evaluation of Stroke Etiology 2023

Uploaded by

Copyright:

Available Formats

REVIEW ARTICLE

LATEST DEVELOPMENTS: Identifying the presence of patent foramen ovale,

412 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

hypertension, age 75 years or older, diabetes mellitus, previous stroke, vascular

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

merely stroke, must be obtained to properly assess potential heritable risk

414 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

are usually not treated with

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

score ≤3), nondisabling (modified Rankin scale, 0 or 1) stroke do not clearly

CASE 1-1 A 93-year-old man with hypertension presented to the emergency

416 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

infarction and is attributable to cardioembolism half of the time and less

CERVICOCEPHALIC ARTERIAL IMAGING

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

neurologic history. He quit cigarette smoking more than two decades

in the right carotid bifurcation extending 18 mm into the internal carotid

418 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

angioplasty, stenting, or surgery of symptomatic vertebrobasilar or intracranial carotid webs.

arteries. The distinction between imaging anterior versus posterior and

cap (CASE 1-2).24

CARDIAC RHYTHM ASSESSMENT

STRUCTURAL CARDIAC IMAGING

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

rare, such as atrial myxoma, papillary fibroelastoma, and valvular vegetations.

echocardiography in the left atrium, left atrial appendage, or aorta. TEE is

generally considered more sensitive and specific than transthoracic

EMBOLIC STROKE OF UNDETERMINED SOURCE

source of embolism).30 ESUS is a subset of cryptogenic stroke. A stroke may be

TESTING FOR INHERITED STROKE SYNDROMES

420 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

venous thrombosis.36 extracranial arteries.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

one-fourth of patients and intracranial mycotic aneurysms occurring in less than

territories, whereas patients with infective endocarditis showed different patterns,

including having a single lesion, a territorial infarction, or disseminated punctate

angiography (CT angiography, MRA, or digital-subtraction catheter angiography)

AUTOINFLAMMATORY CENTRAL NERVOUS SYSTEM VASCULITIS

422 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

263-272. doi:10.1378/chest.09-1584 954-958. doi:10.1161/01.str.0000013069.24300.1d

patient with acute stroke. Continuum (Minneap

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Diagnosis and management of catastrophic

atrial fibrillation after stroke: is there enough 2017;10(4):365-374. doi:10.1080/17474086.

meta-analysis. Neurol Int 2021;13(4):659-670.

424 APRIL 2023

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

You might also like