(Stroke. 2000;31:2641.)
© 2000 American Heart Association, Inc.
Original Contributions |
Use of Transcranial Doppler Ultrasound to Predict Outcome in Patients With Intracranial Large-Artery Occlusive Disease
From the Division of Neurology, Department of Medicine and Therapeutics (K.S.W., H.L., A.W., R.K.), and the Department of Diagnostic Radiology and Organ Imaging (Y.L.C., A.A., W.W.W.L.), the Chinese University of Hong Kong, Shatin, Hong Kong, SAR.
Correspondence to Dr Ka Sing Wong, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR. E-mail ks-wong{at}cuhk.edu.hk
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Abstract |
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Background and Purpose—Intracranial large-artery occlusive disease is the predominant vascular lesion found in stroke patients of Asian, African, and Hispanic ancestry, making it numerically perhaps the most common vascular cause of stroke in the world. Relatively little is known about the clinical significance of finding such lesions. We investigate whether the presence and the extent of these vascular lesions help predict outcome after stroke.
Methods—On the basis of transcranial Doppler of the intracranial arteries with supplementary duplex ultrasound of the carotid arteries, we determined the number of occlusive arteries in the craniocervical circulation of consecutive patients who were hospitalized for acute cerebral ischemia. Patients were followed for 6 months for further vascular events (including transient ischemic attack, stroke, and acute coronary syndrome) or death.
Results—Among 705 consecutive Chinese patients studied, occlusive arteries were found in 345 patients (49%): 258 patients (37%) had intracranial lesions only, 71 (10%) had both extracranial and intracranial lesions, and 16 (2.3%) had extracranial lesions only. Sixty-three (18%) of the 345 patients with occlusive arteries and 35 (9.7%) of the 360 patients without occlusive arteries had further vascular event or death within 6 months. The risk of vascular events or death increased rapidly with rising numbers of occlusive arteries, after adjustment for vascular risk factors and stroke severity (adjusted odds ratio [OR] 1.25 per occlusive artery, 95% CI 1.12 to 1.39). Other independent risk factors included age (OR 1.03 per year of age, 95% CI 1.01 to 1.05) and atrial fibrillation (OR 3.00, 95% CI 1.40 to 6.69).
Conclusions—In patients with predominantly intracranial large-artery occlusive disease, the presence and the total number of occlusive arteries in the craniocervical circulation predict further vascular events or death within 6 months after stroke. Transcranial Doppler ultrasound is an important investigation for the evaluation of patients with stroke in populations at risk of intracranial atherosclerotic disease.
Key Words: arterial occlusive diseases • cerebral ischemia • Chinese • prognosis • ultrasonography, Doppler, transcranial
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Stroke is a heterogeneous disease with a variety of pathophysiological mechanisms. Recent successes in stroke prevention underscore the importance of targeting therapy specifically to remedy the underlying mechanisms, such as carotid stenosis and atrial fibrillation. There are marked differences in the distribution of arterial lesions among different populations. In white individuals, carotid stenosis is a common cause of cerebral ischemia. In contrast, intracranial large-artery stenosis is the predominant vascular lesion found in patients of Asian, African, or Hispanic ancestry.1 2 3 4 5 6 Because of the large populations in Asia and Africa, intracranial large-artery occlusive disease may be regarded perhaps numerically as the most common vascular cause of stroke in the world.
The diagnosis of intracranial arterial stenosis or occlusion requires vascular imaging of the craniocervical circulation. For decades, conventional contrast angiography has been the only method to visualize the intracranial circulation in clinical practice. The invasive nature of conventional angiography and the risk of perioperative complications7 hinder its widespread use in the study of intracranial vascular lesions in stroke patients. Consequently, there has been no large prospective study to assess the clinical significance of the presence of intracranial occlusive disease. The advent of technologies such as transcranial Doppler ultrasound permits studying large numbers of patients safely and reliably in clinical practice.8 9 In the present prospective longitudinal study of consecutive hospitalized patients with cerebral ischemia, we investigate whether the presence and extent of occlusive arteries in the craniocervical circulation predict outcome in terms of further vascular event or death.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study was performed at the Prince of Wales Hospital in Hong Kong, a regional general hospital with accident and emergency service. The protocol was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong. Using transcranial Doppler ultrasound, we examined consecutive patients who were hospitalized with cerebral ischemia (including transient ischemic attack [TIA] and stroke) within 7 days of symptom onset. The baseline examinations included a medical history, physical examination, routine blood biochemistry and blood count, a 12-lead ECG, and a chest x-ray. CT of the brain was performed to rule out intracranial hemorrhage. In particular, we noted any history of smoking, hypertension, diabetes mellitus, ischemic heart disease, atrial fibrillation, TIA, and stroke. We estimated the score of the modified Rankin scale just before the index stroke according to the history provided by the patients or their relatives. On admission to the medical ward, the first reading of the blood pressure and the first score of the National Institutes of Health Stroke Scale performed by a certified personnel were recorded. Because of the need to be examined at the neurosonology laboratory, we excluded patients who required constant bedside monitoring, those who were confused or unable to physically comply with examination, and those who were moribund.
Ultrasound Examination
All enrolled patients were examined by transcranial
Doppler (EME TC-2000). We studied the intracranial large arteries
through the temporal, occipital, and orbital windows by use of a
standardized protocol based on a principle previously
described.10 Briefly, we examined the following arteries
with 4-cm increments: middle cerebral artery (MCA) (temporal window, 52
to 64 mm), anterior cerebral artery (temporal window, 68 to
72 mm), posterior cerebral artery (temporal window, 56 to 64
mm), siphon internal carotid artery (orbital window, 60 to
68 mm), and vertebrobasilar artery (occipital window, 56 to
106 mm). The locations of the 11 studied arterial
segments are illustrated in Figure 1
. We
regarded the vertebral arteries and the basilar artery as one segment
because of the technical difficulty in separating the vertebral
arteries from the basilar artery by transcranial
Doppler. For a similar reason, we categorized vascular lesions in
the terminal internal carotid artery just before the bifurcation as
lesions in the MCA. The extracranial carotid arteries were examined by
a 4-MHz transducer. In addition, a duplex color Doppler examination
of the carotid arteries was also performed. Patients were classified as
having occlusive disease if at least one of the studied arteries showed
evidence of stenosis or occlusion. The criteria for occlusive
arteries were defined by the peak systolic flow velocity as
follows: 
140 cm/s for the MCA, 120 cm/s for the anterior cerebral
artery, 100 cm/s for the posterior cerebral artery and
vertebrobasilar artery, and 120 cm/s for the siphon internal carotid
artery and extracranial carotid artery. Apart from the above velocity
criteria, we took into account the age of patients, presence of
turbulence or musical sound, and whether the abnormal velocity was
segmental. We diagnosed occlusion of the MCA if all basal arteries
except the MCA in question were detectable or if the asymmetry index of
the symptomatic MCA was <-21% compared with the
contralateral MCA.11 Cerebral arteries that could not be
insonated because of poor temporal acoustic windows were regarded as
nonocclusive.
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For classification of MCA stenosis, we defined mild stenosis as systolic peak velocity 140 to 209 cm/s, moderate stenosis as 210 to 280 cm/s, and severe stenosis as >280 cm/s.12 Assessment of the severity of stenosis in other intracranial vessels was not performed because of the lack of published or validated reports. For the duplex ultrasound examination of the extracranial carotid arteries, we used a Philips SD800 ultrasound machine and a 7.5-MHz transducer. The diagnostic criteria for >70% stenosis of the internal carotid artery in our laboratory required a peak systolic velocity ratio of >2.4. The above diagnostic criteria in our neurovascular laboratory were based on our laboratory references, which had a quality assurance program with supplementary angiographic studies. At our laboratory, we performed >1200 transcranial Doppler examinations in a year.
Outcome Assessment
The clinical management of the patients during hospitalization
and after discharge from hospital was left to the attending physicians
who were not involved in the present study. Patients and/or their
relatives were interviewed, and the medical records were examined 6
months after the index stroke. The prespecified outcomes were the
occurrence of further vascular events (including TIA, stroke, or acute
coronary syndrome) or death. We defined TIA and stroke as acute
onset of neurological deficit presumably of vascular origin after
investigations to exclude other causes. Acute coronary syndrome
included myocardial infarction (acute onset of chest pain plus typical
ECG changes and/or raised serum creatine kinase level) and new-onset
angina (acute onset of chest pain plus positive exercise stress test or
>50% stenosis in one of the major coronary arteries
on angiography). Each event was reviewed by an investigator who was
unaware of the results of the ultrasound study. The use of
antiplatelet and anticoagulant agents was recorded at the
6-month follow-up or before death.
Statistical Analysis
For comparison between patients with and without vascular
lesion, a t test was used for continuous variables, such
as age and blood pressure. Cross tabulations by
2 test were used for comparing categorical
variables. To study the effect of the presence and the number of
occlusive arteries on outcome, logistic regression analysis
with all potential variables entered at the same time was used. In
this model, the number of occlusive arteries and age were regarded as
continuous variables. All analyses were performed with the
use of SPSS/Windows version 9.0 statistical software. Statistical
significance was set at P
0.05 by 2-sided
analyses.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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From May 1997, we enrolled 716 Chinese patients within 12 months. All patients were examined by transcranial Doppler and by CT to rule out intracranial hemorrhage. Eleven (1.5%) patients were lost to follow-up and were excluded from the statistical analysis. Of the remaining 705 patients, 360 patients had no occlusive artery detected, and 345 patients had at least 1 occlusive artery. Transcranial Doppler examinations were performed, on average, 4 days after the onset of symptoms and within 7 days for 88% of the patients. One hundred seventy-nine patients (25%) had a poor temporal window that did not allow adequate insonation by transcranial Doppler and resulted in poor acoustic signals. Baseline characteristics, stroke severity, and use of antiplatelet agents are summarized in Table 1
. History of hypertension and previous
cerebrovascular disease were significantly more common in patients with
vascular lesions than in those without. There were nonsignificant
trends for patients with vascular lesions to be older, to have a
history of other vascular risk factors (such as ischemic heart
disease and diabetes), and to have a more severe stroke. By 6 months
after the index cerebral ischemia, 98 patients had died or had
further vascular events. Thirty (30.6%) of these 98 events or deaths
occurred within the first month after cerebral ischemia. The
causes of death and the nature of further vascular events are
summarized in Table 2. The majority of
further vascular events occurred in the cerebral circulation. Recurrent
strokes or TIAs accounted for 60 (61%) of the 98 vascular events or
deaths.
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For the distribution of intracranial and extracranial lesions among
patients with occlusive arteries, 258 (75%) patients had intracranial
vascular lesions only, 71 (21%) patients had both intracranial and
extracranial lesions, and 16 (4.6%) had extracranial lesions only
(Table 3). Among patients with vascular
lesions, the average number of occlusive arteries was 2.7, and the
maximum number was 9 (Table 4). MCA (253
patients), vertebrobasilar artery (139 patients), and anterior cerebral
artery (124 patients) were the 3 most commonly involved vessels. Among
253 patients with occlusive disease in the MCA, 190 patients had
stenosis, and 63 patients had occlusion.
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Patients with vascular lesions were significantly more at risk of
further vascular events or death within the 6-month period after
cerebral ischemia than were patients without occlusive arteries
despite the more frequent use of antithrombotic agents (89% versus
78%, respectively). The adjusted odds ratio for further events or
death in the presence of occlusive artery disease was 1.76 (95% CI
1.11 to 2.79, P=0.016) compared with the absence of
occlusive artery disease, after correction for sex, age, and other
vascular risk factors. The risk of further vascular events or death
rose rapidly with an increasing number of occlusive arteries. The
proportion of patients with an event or death increased from 12.5% for
1 occlusive artery to 50% in patients with 9 occlusive arteries
(P<0.001 by the test for trend). The relationship between
the number of occlusive arteries and the percentage of patients with
further vascular events or death is illustrated in Figure 2. The increased risk remained highly
significant after adjustment for sex, age, diabetes, hypertension,
ischemic heart disease, atrial fibrillation, previous stroke or
TIA, blood pressure on admission, and National Institutes of Health
Stroke Scale by logistic regression analysis (OR 1.25 per
occlusive artery, 95% CI 1.12 to 1.39; P<0.001) (Table 5). Other independent predictors for
vascular events or death were advancing age (OR 1.03 per year of age,
95% CI 1.00 to 1.05; P=0.019) and atrial fibrillation (OR
2.99, 95% CI 1.40 to 6.69; P=0.005).
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The outcome of patients with occlusion and different severity of MCA
stenosis are summarized in Table 6. The risk of further events or death is
related to the status of MCA, with MCA occlusion having the highest
risk (21.4%), MCA stenosis having medium risk (16.6%), and
normal MCA having the lowest risk (12.2%) (2
test for trend, P=0.03) Only patients whose presenting
symptoms were attributable to the MCA stenosis or occlusion
were included in the group with MCA disease. A total of 12 further
ischemic strokes and 8 TIAs occurred within 6 months. Eight
ischemic strokes (67%) and 3 TIAs (37.5%) were considered
relevant to the previous MCA occlusive diseases.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The present study is the first large prospective longitudinal study to assess the clinical importance of finding intracranial large-artery atherosclerotic disease in clinical practice. Previous studies provided inconclusive data on the influence of intracranial vascular lesion on prognosis, partly because most studies were retrospective and studied relatively few patients.13 14 15 16 17 18 In the only prospective study of MCA occlusive disease reported, patients enrolled in the EC/IC Bypass Study19 with minor cerebral ischemia had an annual stroke or TIA rate of 11.7% and annual death rate of
3%. Unfortunately, no control group was
available to assess the impact of MCA occlusive disease because of the
study design of this subgroup analysis. In our cohort, we were
able to compare the prognosis of patients with or without vascular
lesions. We found that the presence of vascular lesions, predominantly
intracranial lesions, significantly increased the risk of further
vascular events or death (OR 1.76).
The recurrent events rate (including TIA, stroke, and all-cause
mortality) of 18% within the first 6 months in patients with
large-artery occlusive disease appears high. However, if only TIA and
stroke are included, the recurrent rate is only 11.6% (Figure 2
). Moreover, recurrent events are known to be much more common
in patients with large-artery occlusive disease than in patients with
lacunar or cardioembolic stroke20 and more common in
nonwhite patients.21 In a recent report of a
population-based study by Petty et al,20 recurrent stroke
occurred in 18.5% of patients with large-artery occlusive disease at
30 days.
For assessment of the severity of arterial occlusive disease (such as carotid stenosis), degree of stenosis has been the mainstay index to identify patients with high risk of recurrent stroke.22 23 24 Another approach for assessing further vascular risk in an individual patient is to assess the total number of occlusive arteries. This approach is possible because many patients in our cohort had multiple arterial involvement. Therefore, it is feasible to use the number of occlusive arteries as a variable to predict outcome. Our data show that the risk of further vascular events or death rises rapidly with an increase in the number of arterial lesions, even after adjustment for sex, age, other vascular risk factors, and stroke severity. This approach to predict outcome is biologically plausible, reflecting quantitatively the burden of occlusive disease in the craniocervical circulation. This finding adds to the current approaches to study vascular lesions, which emphasize degree of stenosis and plaque morphology as predictors of outcome.22 23 24
Transcranial Doppler is a relatively recent advance in imaging that enables measurement of blood flow velocity in large intracranial arteries through temporal, occipital, and orbital portions of the skull.25 It is an established method to diagnose hemodynamically significant stenosis in major intracranial arteries.8 9 It is safe, inexpensive, and easily accessible. However, transcranial Doppler does not provide information regarding the pathological nature of the stenosis. In addition to atherosclerosis, vasospasm after subarachnoid hemorrhage, arteritis, and fibrosis may also lead to increase in blood flow velocity in the cerebral arteries. Although we did not study the pathology of the occlusive lesions, previous autopsy studies of occlusive lesions in cerebral arteries in Asians showed them to be primarily atherosclerotic.26 27 28 Moreover, most of our patients were elderly and had multiple vascular risk factors. Therefore, atherosclerosis is probably the most likely cause of stenosis in our patients.
Lack of a good temporal window for insonation of the cerebral arteries is another inadequacy of the use of transcranial Doppler ultrasound in clinical practice. In the present study, 25% of the patients had poor temporal windows. In this group of patients, some patients might have occlusive disease of the cerebral arteries, but they were inappropriately categorized as having no vascular lesion. Despite this misclassification, which should have weakened the predictive value of the ultrasound, our data clearly demonstrate the clinical importance of vascular studies to predict the course of cerebral ischemia. Recent advances in ultrasound technology, such as the use of contrast-enhancing agents, may remedy this weakness and provide more accurate categorization of patients in the future. In view of the value of transcranial Doppler in predicting outcome as shown in the present study, contrast agents should be used to find stenotic lesions in our population.
It may be difficult for transcranial Doppler to detect a stenosis at the M2 and distal M1 segments of MCA closer than a depth of 51 mm. Inclusion of these lesions may further increase the prevalence of stenosis in our studied population.
Elevated flow velocity of the Doppler signal is the hallmark of an
arterial stenosis. Besides the presence of
turbulent flow, the presence of increase in end-diastolic
velocity with very tight stenoses, flow diversion to
neighboring arteries, and decrease in flow velocity with extremely
tight narrowing are also valuable observations that may enhance our
knowledge of the hemodynamic of individual patient.
However, these changes are difficult to quantify in all patients and
may pose practical problems with statistical analysis.
Moreover, apart from assessment of the MCA, there are no published
criteria for grading stenosis of intracranial arteries, such as
the anterior cerebral and the posterior cerebral arteries and the
siphon section of the internal carotid artery. Therefore, we limited
our analysis to the severity of MCA stenosis. Even for
the MCA, the flow velocity during acute stroke may change rapidly, with
recanalization of emboli or resolving
thrombus.29 Nevertheless, we found a significant trend
toward a worse prognosis for patients with occlusion than for patients
with stenosis, who, in turn, had a worse prognosis than did
patients without stenosis (Table 6.) The number of
events in each category of severity of stenosis was small;
thus, analysis of individual categories might be
inaccurate.
In many ischemic stroke series, survivors usually die from
coronary events rather than recurrent strokes.30
In our patients, there were 44 recurrent strokes and 8 acute
coronary syndromes that occurred in the 6 months after cerebral
ischemia; 9 patients died from recurrent strokes, and only 1
patient died from ischemic heart disease. This observation
mirrors the predominance of cerebrovascular disease over
coronary artery disease in our population. Stroke outnumbered
acute myocardial infarction by 5 to 1 in a previous study of Chinese
patients.31 Therefore, preventing another stroke should
become a priority in the management of patients with cerebral
ischemia in our population. In current practice,
antiplatelet agent is the mainstay of therapy for the prevention of
recurrent stroke. The use of antiplatelet agents had also been
found to be beneficial for Asians with cerebral
ischemia.32 33 However, despite widespread use
(89%) of antiplatelet agents or warfarin in our cohorts, the risk
of further vascular events remains unacceptably high, especially in
patients with multiple occlusive vessels. Our data call for further
study of additional strategies to alleviate the dismal prognosis of
patients with multiple occlusive arterial diseases.
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Acknowledgments |
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This study was supported by the Hong Kong Research Grant Committee (grant No. CUHK 228/96 M). We thank Drs Harold Adams, Jr, Alexander G. Turpie, Brian Tomlinson, and Frank Yatsu for their comments during preparation of this manuscript.
Received April 19, 2000; revision received July 20, 2000; accepted July 20, 2000.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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 R. N. Gundamraj and K. K. Lauer Diagnosis of Intracranial Arterial Stenosis Using Transcranial Doppler Flowmetry Anesth. Analg., June 1, 2004; 98(6): 1776 - 1778. [Abstract] [Full Text] [PDF]
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M. A. Sloan, A. V. Alexandrov, C. H. Tegeler, M. P. Spencer, L. R. Caplan, E. Feldmann, L. R. Wechsler, D. W. Newell, C. R. Gomez, V. L. Babikian, et al. Assessment: Transcranial Doppler ultrasonography: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology Neurology, May 11, 2004; 62(9): 1468 - 1481. [Abstract] [Full Text] [PDF]
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 G. N. Thomas, J. W. Lin, W. W.M. Lam, B. Tomlinson, V. Yeung, J. C.N. Chan, R. Liu, and K. S. Wong Increasing Severity of Cardiovascular Risk Factors With Increasing Middle Cerebral Artery Stenotic Involvement in Type 2 Diabetic Chinese Patients With Asymptomatic Cerebrovascular Disease Diabetes Care, May 1, 2004; 27(5): 1121 - 1126. [Abstract] [Full Text] [PDF]
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 V C T Mok, A Wong, W W M Lam, Y H Fan, W K Tang, T Kwok, A C F Hui, and K S Wong Cognitive impairment and functional outcome after stroke associated with small vessel disease J. Neurol. Neurosurg. Psychiatry, April 1, 2004; 75(4): 560 - 566. [Abstract] [Full Text] [PDF]
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K. S. Wong and H. Li Long-Term Mortality and Recurrent Stroke Risk Among Chinese Stroke Patients With Predominant Intracranial Atherosclerosis Stroke, October 1, 2003; 34(10): 2361 - 2366. [Abstract] [Full Text] [PDF]
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J. F. Arenillas, J. Alvarez-Sabin, C. A. Molina, P. Chacon, J. Montaner, A. Rovira, B. Ibarra, and M. Quintana C-Reactive Protein Predicts Further Ischemic Events in First-Ever Transient Ischemic Attack or Stroke Patients With Intracranial Large-Artery Occlusive Disease Stroke, October 1, 2003; 34(10): 2463 - 2468. [Abstract] [Full Text] [PDF]
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K. S. Wong, H. Li, W. W.M. Lam, Y. L. Chan, and R. Kay Progression of Middle Cerebral Artery Occlusive Disease and Its Relationship With Further Vascular Events After Stroke Stroke, February 1, 2002; 33(2): 532 - 536. [Abstract] [Full Text] [PDF]
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J. F. Arenillas, C. A. Molina, J. Montaner, S. Abilleira, M. A. Gonzalez-Sanchez;, and J. Alvarez-Sabin Progression and Clinical Recurrence of Symptomatic Middle Cerebral Artery Stenosis: A Long-Term Follow-Up Transcranial Doppler Ultrasound Study Stroke, December 1, 2001; 32(12): 2898 - 2904. [Abstract] [Full Text] [PDF]
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