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Original Paper
Received: September 17, 1999
Accepted: February 17, 2000
Cerebrovasc Dis 2000;10:403–408
Cerebral Microembolus Detection in an
Unselected Acute Ischemic Stroke
Population
Christian Lund a Jørgen Rygh b Brynhild Stensrød b Per Morten Sandset b
Rainer Brucher a David Russell a
a Department
of Neurology, The National Hospital, and b Department of Medicine, Ullevaal University Hospital,
University of Oslo, Norway
Abstract
Objective: The aims of this study were firstly to determine prevalence, frequency, and clinical significance of
cerebral microemboli in an unselected acute ischemic
stroke population and secondly to examine how this
information may improve ischemic stroke subtype classification. Methods: We intended to perform transcranial
Doppler (TCD) microembolus monitorings of the middle
cerebral artery (MCA) in the symptomatic hemisphere
for 45 min in 120 consecutive patients with internal carotid artery territory ischemia. The first examination was
performed within 72 h from start of symptoms and the
second 5 B 1 days later. Platelet and coagulation system
activation were measured following TCD monitoring in
38 patients. The strokes were subtyped using the TOAST
classification criteria, and the patients’ clinical status was
assessed at discharge using the Scandinavian Stroke
Scale and the Barthel Index. Results: Microembolus
monitoring was technically possible in 83 (69.2%) of the
ABC
© 2000 S. Karger AG, Basel
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120 patients. Thirty-two (26.6%) patients had an inadequate temporal bone acoustic window or were too restless to allow long-time monitoring. In 5 (4.2%) patients
the relevant MCA was occluded. Twenty-two (26.5%) of
the 83 patients had microemboli despite the fact that
over 90% were receiving an antiplatelet or an anticoagulant treatment. The mean frequency of microemboli was
6.7 B 13.6 per 45 min. Microemboli were more prevalent
in assumed cardioembolic stroke than in other subtypes
of ischemic stroke (p = 0.047). We found no association
between the presence of cerebral microemboli and the
clinical outcome or the parameters for platelet or coagulation system activation. The presence of microemboli
was not associated with in-hospital deaths (p = 0.17),
whereas MCA occlusion was (p = 0.01). Conclusions:
Cerebral microemboli are frequent in unselected acute
ischemic stroke patients despite antiplatelet or anticoagulant treatment. TCD detection of microemboli provides
valuable pathophysiological information and may, therefore, improve current ischemic stroke subtype classification.
Copyright © 2000 S. Karger AG, Basel
Christian Lund, MD
Department of Neurology, The National Hospital
University of Oslo
N–0027 Oslo (Norway)
Tel. +47 22868910, Fax +47 22868890, E-Mail lundchr@online.no
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Key Words
Cerebral ischemia W Embolism W Skull W Ultrasonography W
Transcranial Doppler W Stroke classification
Many clinical trials have been carried out to assess the
efficacy of different treatment regimens in acute ischemic
stroke. The results of these trials have generally been disappointing [1] which may at least partly be due to the fact
that ischemic stroke is not a single disease entity. Although the clinical findings are similar, the pathogenesis
may be very different [2]. Strokes frequently recur, and
the second or third stroke may have an etiology different
from the first [3]. It is hoped, therefore, that ischemic
stroke classification criteria may be improved by information gained from neurosonological and brain imaging
studies [2, 4–6].
Experimental and clinical studies have shown that
Doppler ultrasound may be used to detect arterial emboli
[7, 8]. The demonstration of cerebral microemboli using
transcranial Doppler (TCD) in acute cerebral ischemia
provides evidence that embolic material is entering the
brain which indirectly suggests that the patient’s symptoms may also be due to brain embolism.
The aims of this study were firstly to determine prevalence, frequency, and clinical significance of cerebral microemboli detected in unselected consecutive patients admitted to a stroke unit following acute cerebral ischemia
in the carotid territory and secondly to examine how this
information may improve ischemic stroke subtype classification.
Patients and Methods
Study Population
A total of 120 consecutive patients, 66 women and 54 men with a
mean age of 74 B 10 years were included in the study. All had experienced symptoms of acute cerebral ischemia in the vascular territory of
a carotid artery. The only exclusion criteria was hospital admission
1 72 h after start of symptoms. In Norway, most stroke patients are
served by the stroke unit of their regional hospital. The stroke unit at
Ullevaal University Hospital, Oslo, admits stroke patients from a
catchment area with 193,200 inhabitants (January 1, 1997). This population is comparable with the general Norwegian population with
regard to age and sex distribution [9]. The diagnostic and therapeutic
procedures followed were in accordance with the stroke unit’s normal
guidelines, and the patients or their relatives gave informed consent.
Investigations
A complete clinical neurological examination, a cerebral CT
examination, and a Doppler ultrasound examination of the extracranial carotid arteries were carried out in all patients on admission.
The treating physicians decided whether additional neuroradiological examinations or echocardiography should be performed according to the usual routine of the stroke unit. The number of in-hospital
days and the number of in-hospital deaths were recorded.
404
Cerebrovasc Dis 2000;10:403–408
Neurological impairment and functional outcome at hospital discharge were assessed using the Scandinavian Stroke Scale (SSS) and
the Barthel Index (BI), respectively.
The TOAST classification system was used to subtype the
patients for stroke etiology [10, 11]. This system has five subtypes of
ischemic stroke: (1) cardioembolism; (2) large-artery atherosclerosis;
(3) small-vessel occlusion; (4) stroke of other determined etiology,
and (5) stroke of undetermined etiology.
All SSS and BI ratings, as well as the TOAST subtyping, were
performed by physicians who were blinded to knowledge regarding
the TCD findings. When performing the TOAST classification, historical patient data as well as findings from clinical and supplementary investigations were used.
Hematological and Biochemical Examinations
Blood tests (hemoglobin, platelet count, C-reactive protein, glucose, creatinine, total cholesterol, and triglycerides) were carried out
on admission in all patients. The level of activated coagulation (prothrombin fragment 1+2) and platelet activation (ß-thromboglobulin)
were measured within 12 h after the TCD examination in 38 cases.
Blood for the prothrombin fragment 1+2 analysis was collected in 0.1
vol of 129 mM citrate. The ß-thromboglobulin analysis was collected
in 0.1 vol of CTAD anticoagulant (109 mM citrate, 15 mM theophylline, 3.7 mM adenosine, 0.2 mM dipyridamole). Vacutainer tubes
(Becton Dickinson, Combourg, France) were used. The blood samples were centrifuged (2,000 g, 20 min), and plasma was pipetted off
and stored in aliquots at –80 ° C until analysis. Prothrombin fragment 1+2 was analyzed using a commercial kit (Behringwerke, Marburg, Germany). ß-Thromboglobulin was analyzed using a kit from
Stago (Asnières, France).
TCD Recording
The initial TCD examination was performed within 72 h after
start of symptoms. A second TCD examination was carried out 5 B 1
days later if the patient was still in hospital. Every examination was
made at the bedside in the Stroke Unit by the same observer (C.L.)
using a Pioneer TC 4040 (Nicolet-EME, Überlingen, Germany)
equipped with a 2-MHz monitoring probe. The middle cerebral
artery (MCA) in the symptomatic hemisphere was insonated through
the transtemporal acoustic window with two gates. A stable probe
position was maintained using a fixation device. Both axial sample
volumes were 10 mm in length, the spatial distance between the gates
was 6 mm, and the insonation depths were 55.9 B 2.1 and 49.9 B
2.3 mm, respectively. The fast Fourier transform resolution used was
128 points, the fast Fourier transform-time window overlap was held
constant at 67%, the high-pass filter setting was 120 Hz, and the
sweep speed on screen was 3.1 s. The monitoring time was 45 min.
The Doppler audio signals were recorded on-line onto a digital
audiotape (Tascam DA 38, Tokyo, Japan). When performing the offline analysis, the Doppler audio signals were reintroduced into the
Doppler system using the same instrumentation settings as when the
recordings were performed. The identification of microemboli was
made off-line by an experienced observer (D.R.) who was blinded to
clinical information. International consensus criteria [12, 13], which
were updated by our own group, were applied for microembolus
identification; a relative peak intensity increase of 64 dB from the
background signal, a random appearance in the cardiac cycle, a short
duration (! 0.2 s), unilateral movement in the Doppler spectra, and
typical sound. In addition, the microembolic signals had to appear
with a time lag 1 3 ms in the two sample volumes.
Lund/Rygh/Stensrød/Sandset/Brucher/
Russell
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Introduction
Statistics
We considered a patient to be microembolus-positive, if any cerebral microemboli were detected on one or both examinations. Comparison of group proportions for categorical data within fourfold
tables were calculated with Fisher’s exact test. Continuous nonparametric distributed variables were compared using the Mann-Whitney test and continuous parametric data using the Student t test. The
level of statistical significance was p ^ 0.05. The statistical analyses
were performed with the StatView (version 4.5) statistical program.
The data are presented as mean values B SD.
Results
TCD Monitoring
Cerebral Microembolus Detection
Fig. 1. Eighty-three patients examined for cerebral microemboli
assessed according to the TOAST classification system. The dark columns represent the patients without microemboli; the dotted columns represent the patients with microemboli. C = Cardioembolic
stroke; L = stroke due to large-artery atherosclerosis; S = stroke due to
small-vessel occlusion; U = stroke of undetermined etiology; TIA =
transient ischemic attack.
Incidence and Frequency of Microemboli
Microemboli were detected in a total of 22 (26.5%) of
the 83 patients: in 14 (16.9%) of the 83 patients at the first
examination and in 14 (22.2%) of the 63 patients at the
second examination. Eighteen microembolus-positive patients had two examinations: 6 patients showed microemboli at both examinations and 12 patients at only one
examination. When microemboli were detected, their frequency was 6.7 B 13.6 (range 1–67) per 45 min.
Stroke Subtypes
The 83 patients, in whom TCD microembolus recordings were sucessfully performed, were evaluated for stroke
etiology. Seventy-three (88.0%) of the 83 patients suffered
an ischemic stroke, and 10 (12.0%) patients had a transient ischemic attack (TIA). When the 73 stroke patients
were assessed according to the TOAST classification, we
found that 19 (26.0%) had a cardioembolic stroke, 7
(9.6%) a large-artery atherosclerotic stroke, 17 (23.3%)
stroke due to small-vessel occlusion, and 30 (41.1%)
stroke of undetermined etiology.
Ten (52.6%) patients with cardioembolic stroke, 1
(14.3%) with large-artery atherosclerotic stroke, 3 (17.6%)
with small-vessel occlusion, and 5 (16.7%) with stroke of
undetermined etiology had microemboli (fig. 1). Cerebral
Cerebrovasc Dis 2000;10:403–408
405
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TCD microembolus monitoring was technically possible in 83 (69.2%) of the 120 patients, 39 women and 44
men with an age of 73 B 11 years. Five (4.2%) patients
had a suitable temporal bone window, but an extensive
bilateral TCD examination revealed an occluded symptomatic MCA main stem. Twenty-eight (23.3%) patients
had an insufficient temporal bone window which resulted
in a signal-to-noise ratio which was insufficient for satisfactory long-time monitoring. This was significantly correlated with female sex (p ! 0.001) and high age (p =
0.007). TCD monitoring was impossible in an additional
4 (3.3%) patients because they were too restless.
It was possible to reexamine 63 of the 83 initially
examined patients which gave a total number of 146 TCD
recordings. The first monitoring took place 42.8 B 18.3 h
and the second 149.7 B 35.1 h following symptom start.
During admission, 37 (44.6%) of the 83 patients had an
echocardiographic examination. In 31 cases this examination was normal or revealed only minor structural cardiac
abnormalities. In 6 cases, however, major structural abnormalities (possible cardiac embolic sources) were
found. Twenty-two (26.5%) patients had more than one
cerebral CT or cerebral MRI examination. An internal
carotid artery stenosis (150%) or an internal carotid
artery occlusion was found in 11 (13.3%) of the 83
patients. All of these but 1 were located ipsilateral to the
symptoms. MCA stenosis (150%) was detected in the
symptomatic hemisphere in 2 (2.4%) patients.
At the initial TCD examination 65 (78.3%) of the 83
sucessfully examined patients were receiving an antiplatelet medication: 63 patients acetylsalicylic acid and 2
patients ticlopidine. Twelve (14.5%) patients were anticoagulated: 10 with warfarin and 2 with heparin. Two
(2.4%) patients had a combined treatment with both acetylsalicylic acid and warfarin. Only 6 (7.2%) patients had
neither antiplatelet nor anticoagulant treatment.
Table 1. Clinical outcome parameters
for 67 surviving stroke patients examined
for cerebral microemboli
In-hospital days
SSS score at discharge
BI score at discharge
Patients with
microemboli
(n = 16)
Patients without
microemboli
(n = 51)
p
31.8B37.1
39.7B13.7
16.6B6.3
26.4B26.9
40.3B10.6
17.0B5.5
0.53
0.84
0.84
The maximum (best) scores of SSS and BI are 48 and 20 points, respectively.
Table 2. Biochemical parameters for
coagulation system activation (prothrombin
fragment 1+2) and platelet activation
(ß-thromboglobulin) in 38 stroke patients
(2 with TIA) monitored for cerebral
microemboli
Prothrombin fragment 1+2, nmol/l
ß-Thromboglobulin, ng/ml
Patients with
microemboli
(n = 13)
Patients without
microemboli
(n = 25)
p
1.9B1.0
42.8B24.5
1.5B0.7
39.6B18.0
0.26
0.94
The normal range of prothrombin fragment 1+2 is 0.4–1.1 nmol/l, that of ß-thromboglobulin 10–40 ng/ml.
Outcome
Six (8.2%) of the 73 stroke patients, who had TCD
microembolus monitoring, died in hospital. Three (50%)
of these had cerebral microemboli which was not significant (p = 0.17) with regard to in-hospital deaths. MCA
occlusion was, however, significantly (p = 0.01) associated
with in-hospital death.
The 67 surviving stroke patients who had TCD microembolus monitoring studies were grouped as to whether they had microemboli or not. There was no significant
difference in these two groups with regard to the total
number of in-hospital days, the SSS score, or the BI score
at discharge (table 1).
Hematological and Biochemical Parameters
Assessment of the 83 patients who had TCD monitoring showed no correlation between the presence of microemboli and the following biochemical parameters: hemoglobin, platelet count, C-reactive protein, glucose, creatinine, total cholesterol, and triglycerides. We also found
no significant association between the presence of mi-
406
Cerebrovasc Dis 2000;10:403–408
croemboli and the parameters for coagulation system and
platelet activation (table 2). However, the values for prothrombin fragment 1+2 (1.7 B 0.8 nmol/l, normal range
0.4–1.1 nmol/l, n = 38) and ß-thromboglobulin (41.2 B
21.0 ng/ml, normal range 10–40 ng/ml, n = 38) were both
above the normal range which suggests both activation of
the coagulation system and platelet activation. Anticoagulated patients had a significantly lower value for prothrombin fragment 1+2 as compared with those treated
with antiplatelets alone (0.9 B 0.7 vs. 1.8 B 0.8 nmol/l,
p = 0.03, n = 38).
Discussion
In this study we found that more than 1 of 4 patients
admitted to a stroke unit due to acute anterior cerebral
ischemia had cerebral microemboli during the acute
phase. In other comparable acute TCD studies, the proportion of patients with microemboli during the acute
phase after stroke has shown considerable variation, ranging from 9.3 to 70.7% [14–19]. This large variation may
have several explanations. The patient populations were
not similar in the different studies with regard to age, sex,
and stroke type. In some studies, for example, the mean
age of the patients were 63 years or less which strongly
Lund/Rygh/Stensrød/Sandset/Brucher/
Russell
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microemboli were significantly more prevalent
(p = 0.047) in cardioembolic stroke than in the other
stroke subtypes. Three (30.0%) of the 10 TIA patients had
microemboli.
suggests a certain degree of selection with regard to age
[16, 17, 19]. The patient population in our study had a
mean age of 74 years and represented all patients admitted to a regional stroke unit.
The fact that microembolus detection using TCD is a
relatively new method entails a development with regard
to more exact identification criteria for microemboli.
These have improved with experience during the last
years which may make the value of reported results
dependent to some degree on when the study was carried
out. Results from different studies may be easier to compare in the future, since we now have internationally
accepted criteria [12, 13].
The reported incidence and prevalence of cerebral
microemboli following acute ischemic stroke also depend
on the duration of the TCD monitoring, the number of
examinations carried out, the time interval from symptoms to examination, and on whether the examinations
were performed uni- or bilateral. Ideally, TCD monitoring should be carried out as long as possible during the
first days after admission. We found, however, in a pilot
study that it was practically very difficult in many patients to continue monitoring for longer than 45 min due
to restlessness and lack of cooperation. An additional
problem, especially in older female patients, is the absence of an adequate temporal bone acustic window [20,
21]. This results in a very poor signal-to-noise ratio which
prevents TCD examination or excludes monitoring over
longer periods.
Serial TCD studies have shown that the incidence of
cerebral microemboli is highest closer to symptoms,
whereas the total prevalence in a study population may
increase with repeated examinations [16–18]. However,
in this study we found a slight increase in the incidence at
the second examination which was probably due to the
fact that the second examination did not include patients
who had minor symptoms, since many of these had been
discharged.
The presence of cerebral microemboli following acute
ischemic stroke provides evidence which suggests that the
pathophysiological mechanism for the stroke may be embolic. Traditionally, the clinical diagnosis of brain embolism is made by the combination of clinical features and
the detection of a potential embolic source. Evidence of
cerebral microemboli may make classification of embolic
stroke more exact [22]. This could have important clinical
consequences, since it may facilitate more specific therapeutic decisions. In this study strokes were classified using
the TOAST classificiation system. Cerebral microemboli
were detected in more than half of the patients in whom
the TOAST classification was cardioembolic stroke which
indirectly suggests that this classification was correct.
Bilateral TCD monitoring will provide even more evidence suggesting cardioembolic etiology. Only 1 of the 7
patients with large-artery atherosclerosis (150% stenosis
of a large extra- or intracranial artery) had microemboli,
but the small number of patients in this group excludes
conclusions.
Cerebral microemboli were present in 17.6% of the
patients with lacunar stroke. This suggests that microinfarctions may not always only be due to small-vessel
occlusion following local lipohyalinosis or microatheroma
[16, 19, 23].
The TOAST classification could not be determined in
30 (41.1%) of the stroke patients which underlines the difficulties with present-day classification systems, especially when these are applied to unselected stroke populations
where there are relatively high numbers of elderly patients. Five of the patients in this group had microemboli
which may indirectly suggest an embolic pathogenesis. It
is, therefore, possible that TCD microembolus monitoring may in the future lead to a reduction in the number of
undetermined cases [6].
We did not find a correlation between the presence of
microemboli and the clinical outcome assessed by the SSS
or BI scores at discharge. In a similar study Del Sette et al.
[18] found no association between the presence of microemboli during the acute phase and the 30-day outcome
measured as disability using the Oxford Disability Scale.
A TCD examination during the acute phase of an ischemic stroke will, however, allow the detection of a relevant MCA occlusion which does provide important prognostic information.
It is of interest that cerebral microemboli were detected in 26.5% of the patients despite the fact that over
90% had antiplatelet or anticoagulation treatment or
both. There was no significant correlation between the
presence of microemboli and the markers for coagulation
system and platelet activation in the subgroup of 38
patients studied. These activation measurements suggest,
however, that both activation of the coagulation system
and platelet activation were still present despite treatment
and that the latter was either insufficient or inappropriate
to prevent subclinical microembolus formation in many
of the patients. Larger patient populations should now be
studied to determine not only the prognostic significance
of cerebral microemboli in acute stroke, but also the possibility that their detection may be of help in monitoring
therapy.
Cerebral Microembolus Detection
Cerebrovasc Dis 2000;10:403–408
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407
In conclusion, this study has shown that cerebral microemboli are frequent in unselected acute ischemic
stroke patients despite antiplatelet or anticoagulation
treatment. TCD detection of microemboli gives valuable
pathophysiological information and may, therefore, improve current ischemic stroke subtype classification.
Acknowledgement
This study was supported by The Norwegian Council on Cardiovascular Diseases.
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