A Model to Prevent Fibrinolysis in Patients with Stroke Mimics

Jason Chang, MD,* Mohamed Teleb, MD,* Julian P. Yang, MD,* Yazan J. Alderazi, MD,*
Kristina Chapple, PhD,* James L. Frey, MD,* and Lucas Restrepo, MD, MS†

Background: Many patients with stroke-mimicking conditions receive treatment

with intravenous fibrinolysis (IVF), a treatment associated with potentially serious
complications. We sought to determine if any clinical or radiographic characteristics
can help predict stroke mimics among IVF candidates. Methods: This retrospective
study was carried out at a single institution. Patients treated with intravenous re-
combinant tissue plasminogen activator (rt-PA; n 5 193) were divided into 3 cate-
gories: acute ischemic stroke (n 5 142), aborted stroke (n 5 21), and stroke mimics
(n 5 30). Analysis of variance and the chi-square test were used to assess differences,
while logistic regression models were computed to predict groups. Results: Mimics
treated with rt-PA did not experience complications (intracranial bleeding, systemic
hemorrhage, or angioedema), and had better neurologic and functional outcomes
than stroke patients (P , .05). Several variables helped differentiate strokes from
mimics, including atherosclerosis on computed tomographic angiography (odds ra-
tio [OR] 23.6; 95% confidence interval [CI] 8.4-66.2), atrial fibrillation (OR 11.4; 95%
CI 1.5-86.3), age .50 years (OR 7.2; 95% CI 2.8-18.5), and focal weakness (OR 4.15;
95% CI 1.75-9.8). Other variables decreased chances of stroke: migraine history
(OR 0.05; 95% CI 0.01-0.4), epilepsy (OR 0.13; 95% CI 0.02-0.8), paresthesia (OR
0.1; 95% CI 0.04-0.3), and precordialgia (OR 0.045; 95% CI 0.002-0.9). A regression
model using focal weakness, computed tomographic angiography findings, and
precordialgia had a 90.2% predictive accuracy. Conclusions: IVF has low complica-
tion rates in stroke mimics. Certain clinical characteristics appear predictive of
stroke mimics, particularly normal computed tomographic angiography. If con-
firmed, this may help prevent giving IVF to patients without stroke. Key Words:
Acute ischemic stroke—computed tomographic angiography—emergency
medicine—fibrinolysis—outcomes—recombinant tissue plasminogen activator—
stroke mimics.
Ó 2011 by National Stroke Association

Physicians in the emergency room see several neuro-
logic diseases that can be confused with acute ischemic
stroke (AIS). Time constraints and diagnostic technology
limitations may challenge their ability to establish the
From the *Division of Neurology, Barrow Neurological Institute,
Phoenix, Arizona; and †Department of Neurology, University of
California, Los Angeles, Los Angeles, California.
Received January 11, 2011; revision received March 6, 2011;
accepted April 21, 2011.
Address correspondence to Lucas Restrepo, MD, MS, Department
of Neurology, University of California, Los Angeles, 710 Westwood
Plaza, Los Angeles, CA 90095. E-mail: lrestrepo@ucla.edu.
1052-3057/$ - see front matter
Ó 2011 by National Stroke Association
doi:10.1016/j.jstrokecerebrovasdis.2011.04.018
correct diagnosis. The result is that many patients with
‘‘stroke mimics’’ receive intravenous fibrinolysis (IVF),
a treatment associated with potentially serious complica-
tions. While careful anamnesis and neurologic examina-
tion can unmask stroke mimics, a scrupulous clinical
assessment may squander time, denying potential benefit
to authentic AIS cases.
Fear of treating stroke mimics is a cited reason for with-
holding IVF in the emergency room.1,2 However, stroke
mimics have fewer complications from intravenous (IV)
recombinant tissue plasminogen activator (rt-PA) than
AIS patients. In a study, IVF caused no complications in
7 stroke mimics throughout a 10-year period.3 Another
study found that 13.5% of patients treated with IVF
had stroke mimics, but none developed hemorrhagic

Journal of Stroke and Cerebrovascular Diseases, Vol. -, No. - (---), 2011: pp 1-5 1
2 J. CHANG ET AL.
4
complications or angioedema. Nonetheless, the potential
complications of IV rt-PA cannot be dismissed. There is
a need to correctly identify mimics in a restricted time-
frame. Previous work suggests that such clinical discrimi-
nation is possible. Compared to AIS, mimics are more
likely to feature confusion and seizure history and to
lack lateralizing symptoms.5 However, there are no studies
that aim to predict stroke mimics using simple clinical var-
iables available during the first evaluation in the emer-
gency department.
Here, we compare the clinical characteristics, neuroi-
maging findings and short-term outcomes of stroke
mimics and AIS counterparts treated with IV rt-PA, pro-
posing a simple model to identify patients who should
not receive IVF in the emergency room.
Methods
Study Design
Records from all patients treated with rt-PA from 2007
to 2008 at a tertiary referral center were retrospectively re-
viewed. The local institutional review board approved
this study. Patients were divided into 3 groups: AIS,
stroke mimics, and aborted AIS (AbS). AIS was defined
as sudden focal neurologic dysfunction with evidence of
acute brain ischemia on diffusion-weighted images
(DWIs) or serial head computed tomographic (CT) scans.
AbS was defined as instances of sudden focal neurologic
dysfunction without magnetic resonance imaging (MRI)
signs of acute ischemia that received a final clinical diag-
nosis of AIS. Mimics were patients without acute brain is-
chemia on neuroimaging whose final diagnosis was not
stroke (AIS or AbS). All patients received head CT scans
and, barring renal failure, CT angiography (CTA) of the
intracranial and cervical circulation. For the latter, contig-
uous 0.6-mm axial images were obtained after the IV ad-
ministration of 60 to 80 mL of iopamadol (Isovue-300;
Squibb, New Brunswick, NJ) at 4 mL per second. rt-PA
dosage was 0.9 mg per kg, 10% as bolus within 1 hour
of admission and the remainder administered over 1
hour.6,7 Diagnosis was established by a stroke
neurologist. Brain MRI scans with DWIs were obtained
within 24 hours of presentation.
Outcome Measures
National Institutes of Health Stroke Scale (NIHSS) and
modified Rankin scale (mRS) scores, if not stated in the
chart, were extrapolated from progress notes. Good out-
come was defined as an mRS score of 0 to 2, and poor out-
come was defined as an mRS score of 3 to 6.
Data Analysis
Groups were compared using the chi-square test or
1-way analysis of variance. The Fisher least significant
difference (LSD) test was used for post-hoc analyses.
Standardized residuals were reviewed for post-hoc analy-
ses of chi-square tables. Odds ratios were obtained for
chi-square analyses involving 2 3 2 tables. Logistic and
stepwise regression analyses were used to predict proba-
bility of mimics. Tests were 2-tailed, with significance set
at P , .05. SPSS software (version 1.8; SPSS Inc, Chicago,
IL) was used.
Results
Characteristics of Study Subjects
Of 193 patients receiving IV rt-PA, 142 had AIS, 21 had
AbS, and 30 had mimics. MRI scans were not obtained in
30 AIS patients. Of these, 27 had large artery occlusion
on CTA or MRA, 1 had evolving hypodensities on serial
head CT scan, and no reasons were stated for not pursuing
MRI in the remaining cases. Five stroke mimics did not re-
ceive MRI: 1 left against medical advice, 1 had a pacemaker,
and no reasons were stated for the remainder. Two AbS pa-
tients did not receive MRI, both because of pacers, but both
received follow-up CT imaging (which did not disclose
evolving hypodensities). There was no difference between
time from symptom onset to rt-PA bolus between groups
(Table 1). Mimic etiology included postictal paresis
(n 5 6), complicated migraine (n 5 5), benign paroxysmal
vertigo (n 5 1), meningioma (n 5 2), anxiety (n 5 1), de-
pression (n 5 1), conversion disorder (n 5 1), alcohol intox-
ication (n 5 2), isolated cranial nerve palsy (n 5 1),
multiple sclerosis (n 5 1), transient amaurosis (n 5 1),
rheumatoid arthritis (n 5 1), appendicitis (n 5 1), and un-
identified (n 5 6; 2 leaving against medical advice before
work-up).
Mimics were younger than AIS and AbS patients; be-
ing .50 years of age increased by sevenfold the odds
of AIS (Table 1). Cardiovascular risk factors such as di-
abetes (DM) and atrial fibrillation (AF) were more com-
mon in AIS than mimics, whereas a history of epilepsy
or migraine was more common in mimics. AF in-
creased odds of AIS by 11-fold (Table 2), while odds
of mimics increased with a history of migraine or epi-
lepsy.
Neurologic deficits on admission helped differentiate
AIS from mimics. AIS patients had higher NIHSS scores
than mimics, while focal weakness on presentation con-
ferred a fourfold increase in odds of having AIS (odd ratio
[OR] 4.15; 95% confidence interval [CI] 1.75-9.81; P , .01;
Table 2). Conversely, chest pain and focal paresthesia
were associated with mimics, the latter decreasing odds
of AIS (OR 0.1; 95% CI 0.04-0.3; P , .001). Arterial occlu-
sion on CTA or MRA was observed in 57.8% of AIS pa-
tients but was not detected in AbS or mimics. Diffuse
atherosclerosis on CTA or MRA was associated with
stroke but not mimics (86.6% and 58.8% of AIS and AbS
patients, respectively, v 21.4% of mimics). Atherosclerosis
on CTA increased chances of AIS by almost 24-fold (OR
23.6; 95% CI 8.4-66.2).
STROKE MIMICS AND FIBRINOLYSIS 3

Table 1. Admission variables and patient outcomes

AIS (n 5 142) AbS (n 5 21) MIM (n 5 30) P value

Age* 69.6 6 13.8 71.1 6 14.5 55.6 6 16.2 ,.001y,z

.50 y, n (%) 130 (91.5%) 19 (90.5%) 18 (60%) ,.001
Time to bolus (min) 136.7 6 45 148.3 6 42.4 146.6 6 46.6 NS
Medical history
Diabetes mellitusx 54 (38%) 10 (47.6%) 5 (16.7%) ,.05
Atrial fibrillationx 40 (28.2%) 1 (4.8%) 1 (3.3%) .001
Epilepsyx 2 (1.4%) 0 3 (10%) ,.05
Migrainex 1 (0.7%) 2 (9.5%) 4 (13.3%) ,.01
Previous statinx 41 (28.9%) 12 (57.1%) 8 (26.7%) ,.05
Initial evaluation
NIHSS score on admission* 11.6 6 8.2 5.8 6 4.6 6 6 4.8 ,.001z,k
Focal weaknessx 100 (70.9%) 16 (76.2%) 10 (37%) ,.01
Chest painx 0 1 (4.8%) 3 (10%) ,.01
Paresthesiax 8 (5.7%) 7 (33.3%) 10 (37%) ,.001
CTA occlusionx 78 (57.8%) 0 0 ,.001
CTA atherosclerosisx 116 (86.6%) 10 (58.8%) 6 (21.4%) ,.001
Patient outcomes
NIHSS score at discharge 11.9 6 13.5 1.7 6 2.4 1 6 1.6 ,.001x
mRS score .2 76 (53.5%) 4 (19%) 1 (3.3%) ,.001
Length of stay, days 5.7 6 4.4 3.9 6 2.3 4 6 3.6 ,.05**
Discharged to home 49 (35.3%) 17 (81%) 23 (76.7%) ,.001
Discharged to home or rehab 98 (69.5%) 18 (85.7%) 28 (93.3%) ,.05
Hospice or death 33 (23.7%) 1 (4.8%) 0 (0%) .001
Acute endovascular procedure 24 (16.9%) 0 0 ,.01
Respiratory failure 37 (26.1%) 0 1 (3.3%) ,.001
Any intracranial hemorrhage 24 (16.9%) 0 0 ,.01
Symptomatic intracranial hemorrhage 10 (7%) 0 0 ,.01
Angioedema 4 (2.8%) 0 0 NS

Abbreviations: AbS, aborted acute ischemic stroke; AIS, acute ischemic stroke; CTA, computed tomographic angiography; MIM, mimic;
mRs, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale.
‘‘Atrial fibrillation’’ includes all cases of atrial fibrillation (treated with or without anticoagulants). ‘‘Previous statin’’ refers to the use of a statin
drug before stroke onset. ‘‘Focal weakness’’ refers to abrupt onset weakness of any extremity (but excludes diffuse weakness).
*Analysis of variance.
yP , .001 (difference between AIS and MIM).
zP , .001 (difference between AbS and MIM).
x
Chi-square test.
k
P , .001 (difference between AIS and AbS).

Outcomes Prediction of Stroke Mimics

Outcomes differed depending on the patient group. As
a rule, mimics and AbS had shorter hospital stays and ex-
cellent outcomes. Neither mimics nor AbS patients had
major complications. Symptomatic intracranial hemor-
rhage occurred in 5.2% of all patients (7% of AIS; 0% of
AbS and mimics). AIS cases had higher NIHSS scores at
discharge on average than mimics (11.9 vs 1, respectively;
P ,.001). Among mimics, 27 patients improved neurolog-
ically (90%), 2 (6.7%) had no change, and 1 (3.3%) wors-
ened. The latter patient, an 80-year-old female,
presented with isolated aphasia and was eventually diag-
nosed with complex partial status epilepticus. Her NIHSS
score increased from 1 to 2 because of confusion. Con-
versely, 93 (65.5%) AIS patients improved, 9 (6.3%) pa-
tients had no change, and 40 (28.2%) worsened (14 died).
A logistic regression model containing all variables
with differences between stroke and mimics at a , .01
level (age, DM, chest pain, epilepsy, hypertension, focal
weakness, AF, migraine history, paresthesia, and athero-
sclerosis on CTA) yielded a 97.3% accuracy predicting
AIS and 56% accuracy predicting mimics, with overall ac-
curacy of 91.4% (sensitivity 97.3%, specificity 52%, posi-
tive predictive value 0.9, negative predictive value 0.8,
positive likelihood ratio 2.0, and negative likelihood ratio
0.1). Using forward stepwise logistic regression analysis,
3 variables (atherosclerosis on CTA, focal weakness, and
chest pain) were needed for comparable prediction. This
model correctly identified 95.3% of AIS patients and
60% of mimics, with overall accuracy of 90.2% (sensitivity
95.3%, specificity 60%, positive predictive value 0.9,
4 J. CHANG ET AL.

Table 2. Clinical variables distinguishing stroke and mimics 14

instances. Seizures should be suspected when tonic–
clonic movements precede focal neurologic deficits,
95% 2-sided when episodes are stereotyped, or when altered con-
OR CI P value sciousness occur. However, AIS can occasionally present
Age .50 y 7.2 2.8-18.5 ,.001 with seizures, adding another layer of complexity to the di-
Diabetes mellitus 3.1 1.1-8.5 ,.05 agnostic dilemma.15
Hypertension 2.6 1.13-6 ,.05 Many physicians are reluctant to use IVF because of
Atrial fibrillation 11.4 1.50-86.3 ,.01 concerns of treating patients without stroke. In accord to
Epilepsy 0.1 0.02-0.8 ,.05 previous research, our data suggest that treating stroke
Migraine 0.05 0.01-0.4 ,.01 mimics with IV rt-PA is not necessarily a catastrophic mis-
Previous statin use NS take and could be construed as a tradeoff for treating AIS
CTA atherosclerosis 23.6 8.4-66.2 ,.001 expediently.8-10 Fibrinolysis is given to only 3% to 8.5% of
Focal weakness 4.15 1.75-9.81 ,.01 eligible AIS patients.1,2,8-10 On average, 3 patients per
Paresthesia 0.1 0.04-0.3 ,.001
hospital are treated with IVF every year in the United
Bad outcome 33.4 4.4-251.9 ,.001
States, pointing to a lack of familiarity with the therapy
Discharged to home or rehab 0.2 0.04-0.75 .01
Discharged to home 0.2 0.07-0.41 ,.001 that may contribute to protocol errors.11 Prospects of com-
plete stroke recovery rapidly dissipate as time lapses, and
Abbreviations: CI, confidence interval; CTA, computed tomo- negligible benefit from IVF is expected 4.5 hours after
graphic angiography; OR, odds ratio. symptom onset. Clinicians are therefore compelled to
Chi-square test was used. make a rapid diagnosis based on CT findings, which dur-
OR could not be performed on National Institutes of Health Stroke
ing the initial phases of ischemia may be normal. This
Scale score at admission, CTA occlusion, chest pain, endovascular
intervention, intracranial bleed, or disposition (hospice or death). partly explains why a growing number of patients with-
out stroke are exposed to IVF.
Emergency MRI may reduce diagnostic errors, but at the
negative predictive value 0.7, positive likelihood ratio 2.4, potential expense of procrastination. Anecdotally, no
and negative likelihood ratio 0.1). stroke mimics have been treated at the University of
California Los Angeles Medical Center since an emer-
gency MRI protocol supplanted CT for acute stroke assess-
Discussion
ment. It is presently unclear whether hospitals that base
These data suggest that it is possible to identify stroke their acute stroke management on head CTcan reduce erro-
mimics using several clinical variables that are usually neous treatment resorting to MRI. Nonetheless, ‘‘aborted’’
available on initial evaluation in the emergency room. Fo- and DWI-negative AIS are a constant reminder that MRI
cal weakness, history of AF, and abnormal CTA increased is not a substitute for careful bedside assessment.12 Tele-
the odds of actual stroke, whereas a history of migraine or medicine consultation with stroke neurologists may also
epilepsy and complaints of paresthesia increased chances help decrease the chances of treating mimics with IVF,
of a stroke mimic. Three variables—atherosclerotic but no studies have yet assessed this issue.
changes on CTA, focal weakness, and chest pain—had This study has limitations, including its retrospective
high accuracy at forecasting AIS. The described predic- nature and limited number of patients; as a consequence,
tive models, while fallible, represent clinical aids to we cannot discount the possibility of a type II error. In ad-
prompt a more meticulous consideration of the possibility dition, our classification schemes could distort outcomes.
of a mimic; they are not intended as absolute arbiters of Our patient categorization relied on MRI with DWI,
treatment decisions, but may help decide whether other which infrequently yields false-negative or false positive
diagnostic tests such as emergency MRI are needed before results.12 While our AIS classification was based on neu-
IVF. Our study also confirms that patients with stroke roimaging, that of mimics or AbS was based on the at-
mimics treated with IVF are less likely to have complica- tending physician’s expertise and was therefore
tions than patients with authentic AIS, which is not en- susceptible to human error. However, the AIS and AbS
tirely surprising, because acute neurovascular injury is groups were similar in terms of age and vascular risk fac-
not usually anticipated in stroke mimics. Patients with tors, whereas both stroke groups were strikingly different
myocardial infarction receiving fibrinolysis are less likely from mimics (i.e., the mean age of the latter was 1.5 de-
to develop intracranial hemorrhage than AIS patients.13 cades younger). Our numbers mirror the experience of
In agreement with the available literature,3-5 the most Chernyshev et al,4 suggesting that this figure may be a re-
common cause of diagnostic confusion in our cohort was flection of a high-volume stroke center. In spite of the high
seizures. Unlike stroke, seizures are typically manifested sensitivity of DWI, many small ischemic lesions escape
by ‘‘positive’’ neurologic phenomena (i.e., abnormal detection, particularly in the posterior fossa. We speculate
movements); however, ‘‘negative’’ phenomena, such as that IVF may have promoted full resolution of ischemia in
ictal weakness or aphasia, are also encountered on rare some cases; in other words, therapy may have promoted
STROKE MIMICS AND FIBRINOLYSIS
the conversion of AIS to transient ischemic attack. We
have a relatively high mimic rate compared with other se-
ries. This is explained by our institutional policy, which
has been to treat early and aggressively, even in cases
with ambiguous clinical features. This is similar to other
institutions, such as Memorial Hermann Hospital, in
Houston, Texas.4 With regard to our logistic regression
analysis, the predictive accuracy for AIS was better than
that computed for mimics, perhaps because of a wider
disease spectrum accounting for the latter.
In conclusion, stroke mimics treated with rt-PA have
good outcomes, while a set of simple radiographic and
clinical variables may prevent giving IVF to the wrong pa-
tient. Prospective studies are needed to establish safety of
IVF in stroke mimics and validate the predictive merits of
the clinical models proposed herein.
Acknowledgments: We are indebted to Dr. Jeffrey Saver
for his thoughtful comments.
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