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Thrombolysis in Patients With Acute Stroke Caused by Cervical Artery Dissection
Analysis of 9 Patients and Review of the Literature
Marcel Arnold, MD;
Krassen Nedeltchev, MD;
Matthias Sturzenegger, MD;
Gerhard Schroth, MD;
Thomas J. Loher, MD;
Frank Stepper, MD;
Luca Remonda, MD;
Claudio Bassetti, MD;
Heinrich P. Mattle, MD
Arch Neurol. 2002;59:549-553.
ABSTRACT
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Background Results of recently published studies suggest that intravenous thrombolysis
(IVT) and local intra-arterial thrombolysis (LIT) are feasible procedures
in acute stroke after cervical artery dissection (CAD).
Objectives To describe 9 patients with acute stroke caused by CAD who were treated
by LIT (n = 7) or IVT (n = 2) and to review the literature.
Methods Retrospective analysis of clinical and neuroradiological findings; literature
review from 1980 to present.
Main Outcome Measure Modified Rankin Scale (mRS) score.
Results Of 7 patients treated with LIT, 3 had good outcomes (mRS score of 0-2)
and 4 had bad outcomes (mRS score of 3-6) at 3 months. The 2 patients who
had received IVT recovered to mRS scores of 0 and 3. Twenty-one patients were
identified in the literature. Overall (N = 30), in the IVT group (n = 19),
the outcome was good in 8 patients (42%) and bad in 11 (58%); in the LIT group
(n = 11), 6 patients (55%) had a good outcome and 5 (45%) had a bad outcome.
Overall, 47% (14/30) of the patients (IVT and LIT groups) had a good outcome.
Total mortality was 13% (4/30). There were no secondary complications due
to extension of wall hematoma or angiography. One symptomatic hemorrhage occurred.
Conclusions Thrombolysis is feasible in acute stroke caused by CAD. Local complications
from extension of wall hematoma did not occur. Further prospective studies
are needed to determine the safety and efficacy of thrombolysis in the special
circumstance of acute stroke caused by CAD.
INTRODUCTION
CERVICAL ARTERY dissection (CAD) is a common cause of stroke in young
patients.1-2 Recently, several
authors published reports on single cases or small series of patients that
suggest that intravenous thrombolysis (IVT)3-4
or local intra-arterial thrombolysis (LIT)5-7
can be performed in patients with acute stroke after CAD with limited or no
procedure-related morbidity. We describe an additional 9 patients with CAD
treated with thrombolysis and review the published literature on this therapeutic
approach.
PATIENTS AND METHODS
Between December 1, 1992, and January 1, 2001, 169 patients with acute
ischemic stroke were treated at the University of Berne with local intra-arterial
urokinase (n = 163) or intravenous recombinant tissue plasminogen activator
(n = 6). Inclusion and exclusion criteria have been published previously.8
Local intra-arterial thrombolysis was performed if (1) a clinical diagnosis
of ischemic stroke was established by a neurologist; (2) baseline National
Institutes of Health Stroke Scale score reached at least 4 points (except
for isolated hemianopia or aphasia); (3) computed tomographic scanning excluded
intracranial hemorrhage; (4) 4-vessel cerebral angiogram showed an intracranial
vessel occlusion correlating with the neurological deficit; (5) the expected
interval from symptom onset to LIT was less than 6 hours for carotid territory
stroke and less than 12 hours for basilar artery occlusion; and (6) there
were no individual clinical or laboratory findings advising against thrombolysis.
Intra-arterial urokinase was administered directly into the occluded intracranial
arteries distal to the dissection. Recanalization on posttreatment angiogram
was graded according to Thrombolysis in Myocardial Infarction trial criteria.9
Intravenous thrombolysis was performed if cervical vessel occlusion
precluded access to the target intracranial vessel and only if the procedure
could be done within 3 hours of stroke onset, as provided by the National
Institute of Neurological Disorders and Stroke IVT protocol. Clinical assessment
was performed at hospital admission using the National Institutes of Health
Stroke Scale.10
Of 169 patients treated with thrombolysis, 9 had angiographically identified
dissections before thrombolysis—5 in a single carotid artery, 2 in a
single vertebral artery, and 2 in both vertebral arteries. The 2 patients
with unilateral vertebral artery dissections reported minor neck traumas preceding
the stroke. In the others, no potential cause could be identified. The 7 LIT
patients were treated with urokinase (mean dose, 590 000 IU; range, 400 000
to 1 million IU). Treatment effect was documented by arteriography immediately
after thrombolysis. Two patients with internal carotid artery occlusion from
dissection received intravenous recombinant tissue plasminogen activator (0.9-mg/kg
body weight). After thrombolytic therapy, 7 patients were treated with heparin
in a dose doubling the activated thromboplastin time and 2 were given aspirin
daily (250 mg).
Control computed tomography or magnetic resonance imaging was performed
within 24 hours of thrombolysis. Duplex sonograms were obtained within 12
to 48 hours of thrombolysis to evaluate the status of the dissected artery.
Outcome was assessed by clinical neurological evaluation 3 months after thrombolysis
using the modified Rankin Scale (mRS).11 Modified
Rankin Scale scores of 0 to 2 were defined as "good" outcomes, and scores
of 3 to 6 were defined as "bad" outcomes.
The following complications were considered to be potentially related
to thrombolysis: symptomatic intracerebral hemorrhage, systemic hemorrhage,
and subarachnoid hemorrhage. Lower cranial nerve palsy, Horner syndrome occurring
or progressing after thrombolysis, and clinical deterioration after thrombolysis
suggestive of secondary vessel occlusion or extension of the dissection were
considered to be local complications of thrombolysis.
Review of the English, German, and French literature on CAD and its
treatment with thrombolysis included all publications from 1980 to the present
found in MEDLINE or quoted in articles. Twenty-one additional patients were
identified.3-7
Treatment methods, types and rates of complications, and outcome data were
sufficiently well documented to allow us to analyze these patients in a single
pool with our 9 patients. In 4 studies in which the mRS score was not given,
we interpolated a score based on reported clinical findings. However, systemic
hemorrhage rates were not reported in 2 of the 5 literature sources,3-4 and details regarding recurrent strokes
were not routinely available. Therefore, we restricted these 2 analyses to
the 9 patients from our experience.
RESULTS
Demographic, clinical, and individual outcome data are summarized in Table 1 and Table 2. Figure 1 shows
angiographic results from patient 3 in our study. In the LIT group (n = 7),
4 patients with stenotic vertebral artery dissection had occlusions of the
basilary artery, and 2 patients with stenotic and 1 with occlusive cervical
internal carotid artery dissection had occlusions of the M1 segment of the
middle cerebral artery. Posttreatment angiograms showed complete recanalization
of the intracranial artery (Thrombolysis in Myocardial Infarction grade 3)
in 1 of 7 patients and partial recanalization (grade 2) in 2 of 7. No changes
in the dissected extracranial cerebral arteries were observed in posttreatment
angiograms. There were no angiographic complications related to the dissection.
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Table 1. Demographic and Clinical Outcome Data for 9 Study Patients
With Cervical Artery Dissection Treated by Thrombolysis*
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Table 2. Demographic and Clinical Outcome Data for 21 Literature Review
Patients With Cervical Artery Dissection Treated by Thrombolysis*
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Angiograms of a 40-year-old woman with left anterior middle cerebral
artery (MCA) infarction taken 250 minutes after symptom onset. A, Lateral
view of the left common carotid artery injection shows occlusion of the dissected
left internal carotid artery (ICA), with tapered narrowing of the proximal
lumen. B, Lateral view of the vertebral artery injection demonstrates collateral
blood flow to the anterior cerebral artery of the left side via the left posterior
communicating artery, thus confirming the open lumen of the left distal ICA.
C, Frontal view of the microcatheter advancing through the dissected left
ICA. Contrast injection shows normal lumen of the anterior choroid and anterior
cerebral artery and confirms thromboembolic occlusion of the left MCA. D,
Frontal view during local intra-arterial thrombolysis, with the tip of the
microcatheter in the center of the thrombus in the left MCA showing partial
recanalization after injection of urokinase directly into the clot.
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In the 2 patients with internal carotid artery occlusions treated with
IVT, no posttreatment angiograms were performed. Of 7 patients in our study
treated with LIT, 3 had good outcomes (mRS score of 0-2) and 4 had bad outcomes
(mRS score of 3-6) at 3 months. In 2 patients in our study who underwent IVT,
the individual 3-month mRS scores were 0 and 3. There were no recurrent strokes
during 3-month follow-up in our 9 patients. Of 21 patients described in the
literature, 17 underwent IVT and 4 underwent LIT. After IVT, outcome was good
in 7 patients and bad in 10. After LIT, 3 patients had good outcomes and 1
died.
Overall (study and literature patients), in the IVT group (n = 19),
the outcome was good in 8 patients (42%) and bad in 11 (58%); in the LIT group
(n = 11), 6 patients (55%) had good outcomes and 5 (45%) had bad outcomes.
Overall, 47% (14/30) of the patients had good outcomes. Mortality was 13%
(4/30).
Only 1 patient reported in the literature experienced a symptomatic
intracerebral hemorrhage 36 hours after intravenous recombinant tissue plasminogen
activator therapy. Thus, the rate of symptomatic intracerebral hemorrhage
was 3% (1/30). One patient in our study (11%) experienced an inguinal hematoma
at the site of the arterial puncture. Data on systemic hemorrhage are not
given for the patients described in the literature.7
In neither our series nor the patients described by other researchers
were secondary local complications related to thrombolysis observed. No angiographic
complications related to the dissection were reported.
COMMENT
Thrombolysis is an accepted therapy for acute ischemic stroke.12-13 When it comes to acute stroke caused
by CAD, the experience with thrombolysis is limited. Mostly, the stroke physician
sees patients with CAD before they experience an ischemic deficit, or patients
present late, that is, when the time window for thrombolysis has elapsed.
In such situations, heparin is considered as optimal treatment to prevent
first or recurrent stroke, although use of heparin has never been supported
by a randomized trial.14-16
Anticoagulants in such situations can abolish microemboli detected by transcranial
Doppler sonography, and patients with CAD and microemboli are at higher risk
for recurrent stroke than are those with CAD but without microemboli.17-18
The optimal treatment for the patient with CAD who presents within the
time window when IVT or LIT are therapeutic options has never been studied.
The question arises whether thrombolysis of the embolus lodged in the intracranial
vessel is beneficial to and safe for the patient. There is a danger that thrombolysis
may extend the wall hematoma in the dissected artery and may cause local complications
or further hamper cerebral circulation. In addition, there is the risk of
intracerebral hemorrhage after thrombolysis, as occurs in other patients with
stroke.19
In our small series of 9 patients and in 21 patients described in the
literature who received IVT or LIT for acute stroke caused by CAD, only 1
patient (3%) experienced a symptomatic intracerebral hemorrhage. Therefore,
the risk of intracranial hemorrhage does not seem to be increased compared
with other patients with stroke.
In addition, none of the 30 patients experienced a symptomatic local
complication of the dissected vessel because of thrombolysis. Because routine
cervical magnetic resonance imaging before and after thrombolysis has not
been performed systematically, asymptomatic extension of a wall hematoma or
asymptomatic progressive vessel narrowing cannot be ruled out. However, the
absence of symptoms or signs indicating such events suggests that the dissected
vessel is not damaged further by thrombolytic therapy.
Local intra-arterial thrombolysis involves the general risks of angiography
and an additional risk of fragmentation of a thrombus with displacement of
parts of it to the distal intracranial circulation. In addition, the arteriographic
catheter might be placed into the false, rather than the true, lumen of the
dissected vessel and perforate it. Such complications did not occur in 11
patients treated by LIT.
Because of the small number of patients, the heterogeneity of patients,
and the lack of a control group in our study, it is not possible to address
the efficacy of thrombolysis in patients with acute stroke and dissection.
Overall, 14 (47%) of 30 patients undergoing LIT and IVT had good outcomes.
Thirteen (43%) of these 30 patients had excellent outcomes (mRS score of 0
or 1). Total mortality was 13% (4/30). Although the patients in this series
had mostly severe infarcts, our outcome results are similar to those for the
National Institute of Neurological Disorders and Stroke part 2 subset patients,12 of whom 39% treated with intravenous recombinant
tissue plasminogen activator had an excellent outcome and 17% died. The outcome
data are also comparable to the results of the intra-arterial Prolyse in Acute
Cerebral Thromboembolism II trial,13 in which
40% of the patients treated with recombinant prourokinase had a good outcome
(mRS score of 0-2) and mortality was 25%. Several publications on CAD point
to a good outcome in most patients, even when there are focal cerebral ischemic
events.15 But the outcome depends on the severity
of the initial ischemic deficit. For example, in a series by Bogousslavsky
et al,20 only 12 (40%) of 30 patients had a
good outcome, and 7 patients (23%) died. The 9 patients in our study had moderate
to severe strokes, with a median National Institutes of Health Stroke Scale
score at hospital admission of 18, and the baseline clinical neurological
deficits in the 21 patients with dissection and thrombolysis from the literature
were also mostly moderate to severe. This can partly be explained by the fact
that, in general, younger patients and patients with a severe clinical deficit
are transferred urgently to a stroke unit, whereas hospital admission of patients
with less severe deficits is frequently delayed and beyond the time window
for thrombolysis.
In conclusion, the results of our study and a review of the literature
that includes 21 patients indicate that thrombolysis in CAD involves similar
risks as in other types of stroke. Special or additional risks such as local
complications were not observed. The observations of the use of thrombolysis
in acute stroke caused by CAD are encouraging. Further observational studies
are needed to determine whether thrombolysis is really safe in this setting.
It is unlikely that randomized trials will ever be performed in patients with
this condition. However, indirect comparisons of larger series of patients
with CAD vs patients with stroke from other causes might provide an answer
regarding efficacy. In addition, the question of whether IVT or LIT is more
beneficial to such patients must be resolved as well.
AUTHOR INFORMATION
Accepted for publication December 3, 2001.
Author contributions: Study concept and design (Drs Arnold, Nedeltchev, Sturzenegger, Schroth, Loher, and Mattle); acquisition of data (Drs Arnold, Nedeltchev, Loher,
Stepper, Remonda, Bassetti, and Mattle); analysis and interpretation
of data (Drs Arnold, Sturzenegger, Schroth, Bassetti, and
Mattle); drafting of the manuscript (Drs Arnold,
Nedeltchev, Loher, Stepper, and Mattle); critical revision of the manuscript
for important intellectual content (Drs Arnold, Sturzenegger,
Schroth, Remonda, Bassetti, and Mattle); statistical expertise (Dr Arnold); obtained funding (Dr Mattle); administrative, technical, and material support (Drs Arnold, Sturzenegger, Schroth, and Mattle); study supervision (Drs Sturzenegger, Schroth, Bassetti, and Mattle).
Corresponding author and reprints: Heinrich P. Mattle, MD, Department
of Neurology, University of Berne, Inselspital, CH-3010 Berne, Switzerland
(e-mail: heinrich.mattle{at}insel.ch).
From the Departments of Neurology (Drs Arnold, Nedeltchev, Sturzenegger,
Schroth, Loher, Stepper, Bassetti, and Mattle) and Neuroradiology (Dr Remonda),
University of Berne, Berne, Switzerland.
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