Objective: To identify significant etiological differences between patients with bilateral and unilateral Acute Ischemic
Background: Limited data suggest bilateral AIS is relatively common, accounting for approximately ten percent of AIS. However, stroke etiology as defined by TOAST criteria has not been well defined for patients with evidence of bilateral
AIS on MRI.
Methods: Consecutive patients with AIS presenting to our stroke center (July 2008 to July 2013) were retrospectively identified. Patients with bilateral strokes were defined by restriction on DWI/ADC sequences. Univariate analyses and multivariate logistic regression were performed with appropriate test statistics.
Results: Of the 641 AIS patient who met inclusion criteria, 74 (11.5%) had bilateral AIS findings on MRI. Compared to patients with unilateral AIS findings, patients with bilateral AIS findings had higher rates of cardioembolic disease (30.1%
vs. 21.8%, p< 0.001), hypercoagulable state (8.2% vs. 2.0%, p< 0.001), and vasculitis (6.9% vs. 1.4%, p< 0.001) but did not have
significantly different rates of atrial fibrillation by telemetry or ECG (1.4% vs. 5.8%, p=0.111) or ejection fraction < 30%
(7.6% vs. 3.5%, p=0.113). Patients with bilateral AIS findings were over seven times as likely to have vasculitis (OR=7.11,
95% CI=2.1083-23.9786, p=0.002) and four times as likely to have a hypercoagulable state (OR=4.69, 95% CI 1.6737-13.1173,
p=0.003) as the etiology relative to patients with unilateral stroke, but bilateral AIS findings did not significantly increase the odds of a cardioembolic stroke (OR=1.40, 95% CI 0.7917-2.4715, p=0.248).
Conclusions: Cardioembolic etiology of stroke occurs more often in patients with bilateral acute infarction on imaging,
but only the odds of vasculitis and hypercoagulable state as etiologies were significantly increased by bilateral acute
infarction. Further studies are warranted to understand imaging characteristics of bilateral strokes in regard to etiology.
Acute ischemic stroke; Bilateral stroke; Stroke etiology; Cardioembolic; Hypercoagulable; Vasculitis
The Trial of Org 10172 in Acute Stroke Treatment (TOAST)
classifies subtypes of Acute Ischemic Stroke (AIS) by etiology[
1]. Subtypes of stroke include cardioembolic disease,
large artery atherosclerosis, small vessel occlusion, stroke of
other determined etiology, and stroke of undetermined etiology.
Other determined etiologies of stroke include such
causes as primary or secondary hypercoagulable states, nonatherosclerotic vasculopathies including primary or secondary
cerebral vasculitides, and hematologic disorders involving
acquired autoantibodies or formed blood elements.
Distribution of stroke etiology is generally reported around
25% cardioembolic disease, 20% large artery atherosclerosis,
20% small vessel occlusion, 5% other etiology, and 25%
undetermined etiology[3,4]. The etiology of AIS influences
management of AIS and prognosis after AIS. Thus, TOAST
classification is a valuable tool for the physician treating
stroke.Physicians relyupon clinical features, imaging studies,
and laboratory testing to classify AIS. Magnetic Resonance
Imaging (MRI) increases the accuracy of stroke etiology determination, and Diffusion Weighted Imaging (DWI) has
emerged as a principle means of predicting stroke classification
according to TOAST criteria.
Bilateral stroke is seen on MRI as restriction on DWI
sequences on both sides of the brain, representing multiple
acute infarcts.The pathophysiology of bilateral AIS can involve
embolization of a clot from a pathway common to vasculature
of both sides of the brain, such as the atrium of the heart, the
aortic arch, or, more rarely, bilateral carotid arteries or a single
carotid artery in the presence of a common origin of both
ACAs. Clot embolization corresponds with a TOAST classification
of cardioembolic disease or large artery atherosclerosis
in which a clot showers to multiple vascular territories of the
brain. Bilateral strokes can also be caused byother processes
that limit blood flow in multiple territories, such as vasculitides,
hypercoagulablestates, and hematologic disorders.
Vasculitides are diffuse inflammatory processes that involve
the neurovasculature in stroke patients, hypercoagulable states
involve all vascular beds, including the neurovasculature, and
hematologic disorders restrict blood flow through the neurovasculature.
The incidence of bilateral AIS findings on DWI
approaches10%, yet the most common etiologies of bilateral
AIS are unclear. A study in 2000 found bilateral stroke
to be associated with malignancy, elevated fibrinogen levels,
and elevated hematocrit levels, corresponding to secondary
hypercoagulable states and hematologic disorders classified
in the TOAST scheme as causes of other determined stroke
etiology. In an earlier study, bilateral hemispheric strokes of
the anterior circulation were associated with cardioembolic
disease or bilateral carotid disease. Further, although risk
factor profiling has been performed for subtypes of stroke,
yielding such well-known associations as cardioembolic stroke
and atrial fibrillation, specifically, risk factors for bilateral
versus unilateral AIShave not been thoroughly studied.
The purpose of this study was to determine the relationship
between bilateral AIS findings on DWI sequences and
stroke etiologyin our stroke registry as well as to examine risk
factors and biomarkers forbilateral stroke.
We conducted a single-center cross-sectional study of patients
with AIS admitted to our comprehensive stroke center between
July 1, 2008 and July 31, 2013. Patients with AIS were
identified retrospectively from a prospectively collected stroke
registry. Inclusion criteria were age of at least 18 years
and first-time admission for diagnosis of stroke.Patients were
excluded if MRI was not performed or if there were noacute
stroke findings on MRI. Acute stroke findings were defined as
restriction on DWI/ADC sequences of MRI. Restrictions on
DWI/ADC sequences were classified as unilateral or bilateral.
Stroke risk factors were considered present only if reported
or documented within the electronic medical record. Inpatient
complications were defined as per our prior work[12,13].
Stroke subtype was defined according to Trial of Org 10172
in Acute Stroke Treatment (TOAST) classification. Categorical
variables were assessed using Pearson Chi-square and
continuous variables were assessed with Wilcoxon Rank Sum.
Logistic regression was used to assess the odds of dichotomous outcomes for each TOAST classification separately as predicted
by bilateral MRI findings. IRB approval was obtained from
Tulane University (IRB 447869-2).
Of the 641 AIS patient who met inclusion criteria, 74 (11.5%)
had bilateral acute AIS findings on MRI (Table 1). These patients
had a median age of 62, 52.7% were female, 66.2% were
African American, and demographics were overall similar to
patients with unilateral infarction (Table 2).Affected vascularterritories
of the bilateral infarcts are reported in Table 3.
Compared to patients with unilateral MRI findings, patients with bilateral findings had significantly higher rates of stated
history of Congestive Heart Failure (CHF) (18.9% vs. 7.1%,
p< 0.001) and diabetes (36.4% vs. 29.6%, p=0.025). The only
significant difference between the bilateral compared to unilateral
groups ininvestigatedlaboratory values was factor VIII
level (250.9 vs. 178.3, p< 0.001). Bilateral MRI patients had
worse NIHSS scores at admission (9 vs. 5, p=0.005) and discharge
(5 vs. 2, p=0.001).The distribution of discharge mRS
scores were significantly different, however, median values
were identical (3 vs. 3, p=0.007). Patients with bilateral and
unilateral infarcts had similar mRS scores 90 days post-discharge
(3 vs. 2, p=0.08). Stroke etiology was classified during
the index admission for stroke, and those etiologies diagnosed
as hypercoagulable state or vasculitis were supported by specific
evidence reported in Table 5 and 6, respectively. Compared
to patients with unilateral AIS findings, patients with bilateral
AIS findings had higher rates of cardioembolic disease
(30.1% vs. 21.8%, p< 0.001),hypercoagulable state (8.2% vs.
2.0%, p< 0.001), and vasculitis (6.9% vs. 1.4%, p< 0.001). However,
patients with bilateral AIS findings did not have significantly
different rates of ejection fraction < 30% (7.6% vs. 3.5%,
p=0.113) and actually had lower rates of atrial fibrillation by
telemetry or ECG (5.4% vs. 9.2%, p=0.021). Patients with bilateral
AIS findings were over seven times as likely to have
vasculitis (OR=7.11, 95% CI=2.1083-23.9786, p=0.002) and
four times as likely to have a hypercoagulable state (OR=4.69, 95% CI 1.6737-13.1173, p=0.003) as the defined TOAST etiology
relative to patients with unilateral stroke, but bilateral
AIS findings did not significantly increase the odds of a cardioembolic
stroke (OR=1.40, 95% CI 0.7917-2.4715, p=0.248).
Patients with bilateral AIS findings had significantly more
TEE procedures performed during workup of stroke etiology
than patients with unilateral AIS findings (42.4% vs. 25.5%,
The most common etiology of bilateral AIS in patients in our
stroke registry is cardioembolic stroke. Cardioembolic stroke
occurs when a formed clot, typically in the left atrium, embolizes
and travels into multiple vascular territories of the brain,
effectively showering emboli throughout multiple parenchymal
regions. We diagnosed etiology as cardioembolic per
the Causative Classification of Stroke System, using TTE
and/or TEE to identify potential cardiac sources of infarction.
However, despite a higher rate of cardioembolic classification
in patients suffering bilateral AIS than unilateral AIS, bilateral
AIS did not increase the odds of cardioembolic stroke etiology. Yet, our results show that TEE was performed significantly
more during workup of bilateral AIS etiology (Table 4), suggesting
possible overutilization of resources and presenting
an opportunity to reduce invasive workup, cost, and hospital
length of stay.
Consistent with a previous study showing an association
between hypercoagulable states and bilateral hemispheric
stroke in the anterior circulation, we found that bilateral
AIS increased the odds of hypercoagulable TOAST classification.
Hypercoagulability is a diffuse hematologic process, either
inherited or acquired, by which there is a propensity for
clot formation in the venous and arterial circulatory systems.
Increased likelihood of clot formation renders multiple vascular
territories, including the neurovasculature, susceptible
to infarct. We diagnosed patients at our facility suspected of
having a genetic thrombophilia or a hypercoagulable state by
means of a hypercoagulation laboratory panel (Table 5). Interestingly,
baseline factor VIII levels were significantly increased
in our bilateral AIS population. However, this may be
explained by selection bias due to an increased proportion of
factor VIII levels ordered for patients with findings of bilateral
AIS (Table 4). Factor VIII levels have previously been implicated
in worse stroke outcomes, consistent with our finding
that bilateral AIS patients had worse NIHSS both at presentation
Bilateral AIS also increased the odds of vasculitis as
etiology of stroke in this study. Vasculitidesare a collection of
diseases characterized by an autoimmune state in which the
blood vessels are mistakenly recognized as foreign. Primary
CNS angiitis is confined to the brain, meninges, or spinal
cord whereas secondary CNS vasculitis occurs in the setting
of systemic vasculitis, autoimmune disease, or infectious disease[
16]. The autoimmune state affects the CNS by rendering
multiple neurovasculature territories restrictive to blood flow
either by narrowing of the vessel or formation of clot at sites
of inflammatory insult.In this study, we utilized a conjunction
of clinical presentation, imaging findings, laboratory data, and
history of comorbid conditions to provide evidence for the diagnosis
of vasculitis (Table 6). Biopsy was not performed to
Our study is limited by our sample size and low occurrence
rate of bilateral infarcts, which may prevent detection
of differences between groups. Our retrospective study design
permits only hypothesis-supporting results and conclusions
cannot be drawn. Further, this study was performed in a single
urban tertiary stroke center, which limits the generalizability
to similar populations.
In summary, we expected the presence of bilateral acute
infarction to predict cardioembolic pathophysiology, we found
that the presence of bilateral stroke increased the probability of
hypercoagulable state and vasculitis as the determined etiology
of stroke. While cardioembolic strokes were more common
in the bilateral stroke group of patients, the presence of bilateral
stroke did not increase the probability of cardioembolic
stroke as the etiology compared with unilateral stroke. Further
studies are warranted to correlate bilateral infarcts with their
etiology, pathophysiology, and clinical management.
The authors have no financial considerations to disclose.