Deteriorating Ischemic Stroke in 4 Clinical Categories

Classified by the Oxfordshire Community Stroke Project

Hideaki Tei, MD; Shinichiro Uchiyama, MD; Kuniko Ohara, MD; Michiko Kobayashi, MD;
Yumiko Uchiyama, MD; Megumi Fukuzawa, MD

Background and Purpose—The aim of this study was to investigate the frequency, possible predictive factors, and
prognosis of deteriorating ischemic stroke in 4 clinical categories according to the classification of the Oxfordshire
Community Stroke Project (OCSP).
Methods—A total of 350 patients with first-ever ischemic stroke who presented within 24 hours of onset were enrolled.
Based on the OCSP criteria, cerebral infarctions were divided into the following 4 clinical categories: total anterior
circulation infarcts (TACI), partial anterior circulation infarcts (PACI), lacunar infarcts (LACI), and posterior circulation
infarcts (POCI). Clinical deterioration was defined as a decrease of ⱖ1 points in the Canadian Neurological Scale (CNS)
(in TACI, PACI, and LACI) or Rankin Scale (RS) (in POCI) during 7 days from the onset. In each clinical category,
deteriorating (D) and nondeteriorating (ND) patients were compared in terms of their background characteristics, risk
factors, vital signs, laboratory data, and cranial CT at the time of hospitalization. The acute-phase mortality and
functional outcome were also compared.
Results—The subjects comprised 86 patients (24.6%) with TACI, 63 (18.0%) with PACI, 141 (40.3%) with LACI, and 60
(17.1%) with POCI. Overall, 90 patients (25.7%) deteriorated. The frequency was very high in TACI (41.9%), followed
by LACI (26.2%) and POCI (21.7%), whereas it was very low in PACI (6.3%). There were some clinical variables that
differed significantly between D and ND groups. In the patients with TACI, early abnormalities of the cranial CT and
significant stenoses in corresponding arteries were more frequent in the D than the ND group. In those with LACI, the
CNS and hematocrit were lower in the D than the ND group. In those with POCI, cerebral atrophy was more severe and
significant stenoses in vertebrobasilar arteries were more frequent in the D than ND group. The mortality of the D groups
of patients with TACI and POCI exceeded 35%, and the functional outcome was worse in the D group than in the ND
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group of patients with TACI, LACI, and POCI.

Conclusions—The frequency of deterioration in acute ischemic stroke significantly differed among the OCSP subgroups,
and deterioration worsened the prognosis. There were some factors that could predict deterioration: early CT findings
in TACI, large-artery atherosclerosis in TACI and POCI, and stroke severity in LACI. Further research to find
sophisticated radiological and chemical markers appears to be needed. (Stroke. 2000;31:2049-2054.)
Key Words: cerebral infarction 䡲 stroke classification 䡲 stroke outcome

N eurological progression or deterioration during the first

hours to days of cerebral infarction is common and
produces serious clinical problems. The frequency of deteri-
oration varies, ranging from 12% up to 42% among several
reports,1 and the underlying mechanism has yet to be unani-
mously defined.1– 4
Diagnostic criteria and the time from onset of symptoms to
the first evaluation are the major factors of the variation of the
frequency of worsening.1–3,5 Although most studies have
enrolled all patients with various degrees of severity into a
nonstratified group and analyzed them with respect to dete-
rioration or progression,6 different subgroups in symptoms
and severity apparently exist at onset in patients with cerebral
infarction. It has been suggested that the mechanism of
worsening and its outcome differ between subgroups with
different symptoms and severity.7
In 1991, the Oxfordshire Community Stroke Project
(OCSP) proposed 4 easily defined subgroups of cerebral
infarction.8 These definitions are based solely on presenting
symptoms and signs and have been estimated as easy to
apply, having good interobserver reliability, ability to predict
the prognosis, and good correspondence to the underlying
pattern of vascular origin and cranial CT.9 –11 We have
recently reported the frequency, possible predictive factors,
and prognosis of clinical progression in 4 clinical subgroups
according to the OCSP in 250 patients with acute ischemic

Received March 6, 2000; final revision received May 23, 2000; accepted May 30, 2000.
From the Department of Neurology, Toda Central General Hospital, Saitama, Japan (H.T., M.F.); Department of Neurology, Neurological Institute,
Tokyo Women’s Medical University, Tokyo, Japan (S.U., K.O., Y.U.); and Department of Neurology, Teikyo University Hospital, Tokyo, Japan (M.K.).
Correspondence to Hideaki Tei, Department of Neurology, Toda Central General Hospital, 1-19-3 Hon-cho, Toda City, Saitama 3350023, Japan.
© 2000 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org

2049
 2050 Stroke September 2000
stroke.7 In the present study, we added 100 patients and
analyzed those aspects in deteriorating ischemic stroke.
Subjects and Methods
We investigated 350 patients with first-ever acute ischemic stroke
within 24 hours of their symptoms, which lasted until entry, and who
were admitted to the Department of Neurology, Toda Central
General Hospital, from May 1994 to August 1999. There were 206
men and 144 women, aged 32 to 92 years (average 67 years). These
patients were prospectively studied. All the patients underwent a
cranial CT at the time of entry to rule out cerebral hemorrhage. The
entry time was defined as the time when the first CT was performed.
According to the definition of OCSP,8 patients were classified into
the following 4 clinical subgroups: total anterior circulation infarcts
(TACI), partial anterior circulation infarcts (PACI), lacunar infarcts
(LACI), and posterior circulation infarcts (POCI) by 1 neurologist
(H.T.). Patients whose symptoms were hard to classify into any of 4
subgroups (uncertain cases9) were excluded (there were 20 such
patients during the study period). Each patient was examined daily
by the same neurologist during the first 7 days, and the clinical
deterioration was defined as a decrease of ⱖ1 point in the Canadian
Neurological Scale (CNS)5,12,13 in patients with TACI, PACI, and
LACI, or a worsening of ⱖ1 point on the Rankin Scale (RS)13 in
patients with POCI during the 7 days compared with the scores at
entry. We applied the CNS, which has been used most frequently in
the assessment of deteriorating stroke to patients with TACI, PACI,
and LACI.1–3,5 Many symptoms such as sensory deficit or ataxia are
systematically neglected in most established neurological scales,14
and these domains affect most prominently cases of posterior
circulation syndrome. We considered that the RS, which is an
assessment scale of disability, is more suitable for evaluating the
deterioration in patients with POCI. We followed up each patient
until 2 months later or hospital discharge. Patients who had recurrent
cerebral infarction in another vascular territory during observation
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period were excluded. Standard blood and coagulation tests were
performed in all patients. Patients underwent cardiac and large-artery
investigations as follows: 12-lead ECG in all patients (100%),
transthoracic echocardiography in 340 patients (97.1%), 24-hour
Holter ECG in 108 (30.9%), 3-D MR angiography (phase contrast,
extracranial, and intracranial) in 279 (79.7%), conventional angiog-
raphy in 3 (0.9%), and carotid ultrasonography (B-mode) together
with 3-D CT angiography (intracranial) in 31 patients (8.7%).
In each clinical subgroup, deteriorating (D) and nondeteriorating
(ND) patients were compared in terms of the following variables:
background characteristics (age, gender, time from onset, CNS or RS
at entry, antithrombotic therapy before onset); vital signs at entry
(systolic blood pressure, diastolic blood pressure, body temperature);
risk factors (hypertension [past use of antihypertensive agents or
blood pressure of ⬎160/90 mm Hg at least twice before onset],
diabetes mellitus [use of insulin or oral hypoglycemic agents, fasting
blood glucose ⱖ140 mg/dL, or random blood glucose ⱖ200 mg/dL],
current cigarette smoking, transient ischemic attack); laboratory data
(C-reactive protein, blood glucose, glycosylated hemoglobin, hemat-
ocrit, fibrinogen, total cholesterol, triglyceride, high-density lipopro-
tein; cranial CT at entry (early abnormality15 [early infarction, early
parenchymatous signs], leukoaraiosis score [according to the method
of van Swieten et al16], atrophy [mean of the bifrontal, bicaudate, and
biparietal indices17], silent infarctions [patchy, low-density areas that
are sharply demarcated from the surrounding tissue, irrelevant to the
current symptoms]; cardiac evaluation (ⱖ1mm depression of ST
segment on ECG, potential cardiac sources of embolism18); large-
artery disease (ⱖ50% stenosis or occlusion of the corresponding
artery); and prognosis (acute-phase mortality [within 1 month], RS at
discharge or 2 months from the onset (patients who died were
excluded).
The following antithrombotic agents were administered during the
first 7 days from entry: 147 patients (42.0%) were given anticoagu-
lants (low-molecular-weight heparin, warfarin, or unfractionated
heparin), 148 (42.3%) were given antiplatelet agents (aspirin, ticlo-
pidine, or sodium ozagrel, a thromboxane A2 synthetase inhibitor19),
TABLE 1. Frequency of Deterioration in 4 Clinical Categories
based on OCSP Classification
Category No. D
TACI 86 36 41.9%*
PACI 63 4 6.3%†
LACI 141 37 26.2%
POCI 60 13 21.7%
Total 350 90 25.7%
*P⬍0.01 compared with PACI and POCI, P⬍0.05 compared with LACI;
†P⬍0.01 compared with other 3 categories.
and 38 (10.9%) were given argatroban,20 a thrombin inhibitor.
Continuous data were presented as mean⫾SD. The Student t test was
used in univariate analysis for continuous variables and the␹2 test for
noncontinuous variables. A level of P⬍0.05 was regarded as
statistically significant.
Results
The subjects comprised 86 patients (24.6%) with TACI, 63
(18.0%) with PACI, 141 (40.3%) with LACI, and 60 (17.1%)
with POCI (Table 1). Overall, 90 patients (25.7%) deterio-
rated. The frequency was very high in TACI (41.9%),
followed by LACI (26.2%) and POCI (21.7%), while the
frequency was very low in PACI (n⫽4, 6.3%); these differ-
ences were statistically significant (Table 1). With respect to
antithrombotic therapy during the first week, in the D group,
46 patients (51.1%) were treated with anticoagulants, 30
(33.3%) with antiplatelet agents, and 14 (15.6%) with ar-
gatroban; in the ND group, 101 patients (38.8%) were treated
with anticoagulants, 118 (45.4%) with antiplatelet agents, and
24 (9.2%) with argatroban. In the D group, 13 patients were
treated with 2 categories of antithrombotic agent. There were
no significant differences in the antithrombotic treatments
during the first week between the D and ND groups of each
clinical category.
D versus ND group comparisons were not performed for
the PACI group because the number of patients in the D
group was too small (4 versus 59).
Table 2 describes background characteristics and risk
factors in each D and ND group of the 4 clinical categories.
The only difference between D and ND groups was the CNS
score at entry in LACI, which was more severe in D group.
No other differences were detected between D and ND groups
of TACI, LACI, and POCI in the background characteristics
or risk factors.
Table 3 shows the comparisons of laboratory data, cranial
CT, cardiac, and large-vessel evaluation in the D and ND
groups of each subclassification. Among TACI patients, early
abnormalities of the cranial CT and significant stenoses on
corresponding arteries were more frequent in the D group
than in the ND group. In the LACI patients, a difference was
observed only in hematocrit, which was lower in the D group
than in the ND group. In POCI patients, cerebral atrophy was
more severe and significant stenoses in vertebrobasilar arter-
ies were more frequent in the D group than in the ND group.
Other variables were not different among the D and ND
groups of patients with TACI, LACI, and POCI.
 Tei et al Deteriorating Ischemic Stroke in 4 OCSP Categories 2051

TABLE 2. Background Characteristics and Risk Factors in D and ND Groups, by OCSP Category
TACI LACI POCI

D ND PACI D ND D ND
(n⫽36) (n⫽50) (n⫽63) (n⫽37) (n⫽104) (n⫽13) (n⫽47)
Age 72.7 (13.4) 71.3 (9.8) 68.0 (10.5) 64.8 (10.3) 64.7 (11.6) 64.9 (9.5) 64.0 (13.0)
Gender, m⬊f 21⬊15 22⬊28 37⬊26 17⬊20 65⬊39 10⬊3 34⬊13
Time from onset, h 6.4 (6.8) 3.9 (3.9) 9.3 (8.5) 12.8 (8.2) 11.9 (8.8) 9.8 (7.8) 9.6 (8.2)
CNS or RS at entry 5.5 (5.3) 4.8 (1.5) 8.5 (1.4) 9.0 (1.0) 9.4 (1.0)* 3.5 (0.6) 3.0 (1.0)
Preantithrombotic therapy, % 11.1 18.0 19.0 5.4 8.7 15.4 12.8
Systolic blood pressure, mm Hg 167.7 (39.3) 158.4 (27.4) 153.6 (25.5) 165.1 (19.6) 167.1 (27.7) 177.8 (20.0) 164.3 (36.3)
Diastolic blood pressure, mm Hg 91.1 (17.8) 88.5 (17.4) 83.0 (16.3) 92.5 (15.5) 93.6 (16.5) 95.2 (12.6) 89.7 (21.5)
Body temperature, °C 36.0 (0.9) 36.3 (0.7) 36.4 (0.7) 36.2 (0.6) 36.3 (0.5) 36.3 (0.6) 36.3 (0.6)
Hypertension, % 61.1 48.0 42.9 56.8 66.3 61.5 63.8
Diabetes mellitus, % 19.4 10.0 17.5 21.6 19.2 38.5 14.9
Current smoker, % 33.3 32.0 41.3 43.2 51.9 46.2 51.1
Transient ischemic attack, % 31.6 30.0 30.1 13.5 14.4 30.8 10.6
Values in parentheses are SD.
*P⬍0.05.

Table 4 shows the prognosis in D and ND groups of the 4
clinical categories. The mortality of the D group of patients
with TACI and POCI exceeded 35%, and the functional
outcome was worse in the D group than in the ND group of
patients with TACI, LACI, and POCI.
Discussion
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The main factor for this difference appears to be the time
from the onset of symptoms to the first evaluation. Worsening
of the neurological deficits are probably more frequently
detected when the patients are assessed earlier.2 Recent
studies that used 24 hours from onset as the inclusion
criterion reported that the worsening rate was from 27.0% to
33.6%,6,21–24 values that are comparable with our results.

The frequency of deterioration in acute ischemic stroke Another factor might be the diagnostic criteria of deteriora-
differs among several reports, ranging from 12% up to 42%.1 tion. Although most studies have applied established neuro-

TABLE 3. Comparisons of Laboratory Data, Cranial CT, Cardiac, and Large-Vessel Evaluation in D and ND Groups, by OCSP Category
TACI LACI POCI

D ND PACI D ND D ND
(n⫽36) (n⫽50) (n⫽63) (n⫽37) (n⫽104) (n⫽13) (n⫽47)
C-reactive protein, mg/dL 1.3 (2.1) 0.7 (1.3) 0.8 (2.4) 0.6 (1.9) 0.5 (1.7) 1.8 (3.8) 0.9 (2.5)
Blood glucose, mg/dL 163.9 (79.0) 136.0 (38.0) 137.9 (66.6) 146.3 (70.0) 136.8 (69.8) 181.4 (79.5) 134.5 (43.4)
HbA1c, % 5.9 (1.5) 5.5 (1.0) 6.2 (2.0) 6.4 (2.4) 6.7 (5.5) 6.0 (1.6) 5.5 (1.3)
Hematocrit, % 39.9 (4.7) 40.3 (4.5) 41.5 (4.7) 40.0 (4.3) 41.8 (4.0)* 41.0 (7.0) 41.8 (4.6)
Fibrinogen, mg/dL 388.6 (124.9) 346.1 (99.4) 331.6 (85.5) 325.9 (93.1) 307.3 (76.8) 364.5 (108.7) 333.9 (76.6)
Total cholesterol, mg/dL 180.4 (45.0) 189.3 (40.4) 190.1 (36.0) 216.0 (40.9) 200.8 (40.0) 200.7 (52.3) 200.8 (39.9)
Triglyceride, mg/dL 109.9 (60.1) 97.4 (50.4) 118.0 (62.9) 122.6 (66.4) 126.2 (75.1) 135.9 (45.5) 121.0 (47.7)
HDL, mg/dL 52.6 (16.5) 51.3 (13.0) 48.5 (15.1) 52.6 (15.2) 50.6 (13.9) 53.7 (17.7) 49.1 (16.7)
ST depression on ECG, % 30.6 30.0 11.1 13.5 11.5 7.7 21.3
Cardioembolic source, % 50.0 66.0 42.9 2.7 5.8 15.4 23.4
Cranial CT, %
Early abnormality 86.1† 18.4 57.1 37.8 44.2 30.8 34.0
Leukoaraiosis 1.2 (1.1) 1.3 (1.1) 0.9 (1.1) 1.5 (1.3) 1.1 (1.1) 0.8 (1.0) 1.0 (1.2)
Atrophy 0.34 (0.03) 0.33 (0.03) 0.33 (0.03) 0.33 (0.04) 0.33 (0.03) 0.36 (0.02)* 0.33 (0.03)
Silent infarction 27.8 26.0 17.5 32.4 34.6 23.1 27.7
Significant stenosis on (n⫽19) (n⫽43) (n⫽62) (n⫽36) (n⫽101) (n⫽7) (n⫽45)
corresponding artery, % 68.4* 34.9 51.6 41.7 38.6 71.4* 31.1
Values in parentheses are SD. HbA1c indicates glycosylated hemoglobin; HDL, high-density lipoprotein.
*P⬍0.05; †P⬍0.01.
 2052 Stroke September 2000
TABLE 4. Prognosis for D and ND Groups, by OCSP Category
TACI
D ND
(n⫽36) (n⫽50)
Acute phase mortality, % 47.2* 0.0
Rankin Scale score at 2 months 4.7 (1.0)* 3.9 (1.2)
Values in parentheses are SD.
*P⬍0.01; †P⬍0.05.
logical scales such as the CNS, the National Institutes of
Health Stroke Scale (NIHSS), or the Scandinavian Neurolog-
ical Scale,5 some studies did not use these scales.1,14 We
applied the CNS and RS because of the reasons detailed in the
Subjects and Methods section.
Except for a few studies, any patients with various degrees
of severity have been enrolled into a nonstratified group and
analyzed in the studies of deteriorating or progressing stroke.6
We sought to analyze the deteriorating ischemic stroke by
subdividing patients into 4 groups according to the criteria of
the OCSP. Yamamoto et al14 analyzed the clinical worsening
in cerebral infarction resulting from different causes (ie,
cardioembolic, large-artery atherosclerosis, small-artery dis-
ease, or other causes), whereas the precise diagnosis of these
subtypes is very difficult in the early phase.11,18 Therefore, we
analyzed deteriorating ischemic stroke by the symptomatic
subgroups of the OCSP criteria.
The frequency of deterioration was very high in TACI,
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followed by LACI, and then POCI, whereas it was very low
in PACI. We previously reported11 that the mechanism of
infarction in PACI was either cardioembolic or large-artery
atherosclerosis in equal numbers, whereas in TACI ⬎60% of
cases were caused by cardioembolism and only 20% caused
by large-artery atherosclerosis. It has been suggested that the
thrombus from the heart is generally larger than that from the
large vessel.25,26 The low frequency of deterioration in PACI
could be explained by relatively small emboli from the heart
or from the large artery. Favorable short-term prognosis in
PACI patients was described by the first report of the OCSP,8
and Pinto at al27 also reported a low frequency of worsening
in PACI (4%). However, Dahl et al28 reported that, among the
4 OCSP groups, the progression was most frequent in the
PACI group. Further studies are warranted. It has been
suggested that the early progression and final outcome were
dependent on the initial stroke severity.6,13,29 DeGraba et al6
recently reported that only14.8% of patients with the NIHSS
score of ⱕ7 experienced progression, whereas 65.9% of
patients with an NIHSS score of ⬎7 experienced progression.
According to the NIHSS, the majority of patients with TACI
would be scored ⬎7 and the majority of those with PACI
would be scored ⱕ7. The high frequency of worsening in
TACI and the low frequency of worsening in PACI in our
results were consistent with those reported by DeGraba et al.6
The fact that the CNS at entry was significantly lower in
the D than in the ND group of patients with LACI again
implies the importance of initial stroke severity as a determi-
nant of the worsening in acute ischemic stroke. According to
the NIHSS, LACI patients with mild severity would be scored
LACI POCI
PACI D ND D ND
(n⫽63) (n⫽37) (n⫽104) (n⫽13) (n⫽47)
1.6 2.7 0.0 38.5* 0.0
1.9 (0.9) 2.7 (1.1)† 1.8 (0.9) 2.8 (1.0)* 1.7 (1.0)
ⱕ7, whereas those with dense severity would be scored ⬎7.
The intermediate frequency of worsening of LACI between
TACI and PACI in our study is consistent with the suggestion
of DeGraba et al.6
With respect to the comparison of the D and ND groups in
each category, early abnormalities of the cranial CT were
more frequent in the D group than in the ND group of patients
with TACI. It has been reported that early abnormalities on
CT, such as hypodensity, hyperdense middle cerebral artery
sign, or mass effect are important predictors of deteriora-
tion.1,3–5,29 –31 Given that it was the case only in TACI group,
it could be speculated that edema (cytotoxic and vasogenic) is
the important mechanism of clinical deterioration in TACI.5
Another difference between the D and ND groups in TACI
patients was that the significant stenosis of the large artery
was more frequent in the former group. Thrombus propaga-
tion or insufficient collateral blood supply might be another
important mechanism in the worsening of TACI.4,5 However,
because not all the patients in our study could undergo
large-artery evaluation, this speculation must be reevaluated
in future studies.
Except for the difference in the CNS score at entry,
hematocrit was significantly lower in the D than the ND
group of LACI patients. This was an unexpected result. There
has been no such report previously in the study of deterio-
rating stroke. Because mean hematocrit was 40.0⫾4.3 in the
D group and 41.8⫾4.0 in the ND group, which were both
within normal range, it is hard to find the significance of this
difference in LACI patients. There were no other variables
that significantly differed between the D and ND groups of
patients with LACI. The mechanism of worsening in LACI
patients is unclear. Nakamura et al24 recently analyzed
progressive motor deficits in 92 patients with lacunar infarc-
tion within 24 hours of onset in the internal capsule or the
corona radiata. They found that the frequency of progression
was 27%, similar to our finding, and that the blood glucose
was higher, the motor deficits at entry were more severe, and
the lesion volume on CT was larger in the progressing group
than in stable group; some of these results are consistent but
others are inconsistent with our results. Because the fre-
quency of significant stenosis of large artery did not differ
between the D and ND groups, the macrovascular mechanism
in deterioration in LACI is unlikely, although a microvascular
mechanism4 or branch atheromatous disease32,33 may play an
important role in the LACI patients.
In the patients with POCI, cerebral atrophy was more
severe and significant stenosis in vertebrobasilar arteries was
more frequent in the D than in the ND group. These results
 Tei et al Deteriorating Ischemic Stroke in 4 OCSP Categories
imply that unlike in LACI, macrovascular mechanisms play
an important role in the clinical worsening in POCI patients.
We speculate that cerebral atrophy caused by longstanding
hypoperfusion due to large-artery atherosclerosis might un-
derlie the worsening in POCI patients. It has been suggested
that large-artery atherosclerosis of extracranial or intracranial
vertebrobasilar arteries is more frequent in posterior circula-
tion infarcts than previously thought.34 –36
Other reported variables concerning the neurological pro-
gression, such as body temperature,23,37 fibrinogen,23 blood
glucose,24,38,39 diabetes mellitus,22 blood pressure,4,22,39 tran-
sient ischemic attack,14 and higher brain dysfunction,40 did
not significantly differ between the D and ND groups in any
category. Overall patients’ analysis would alter the results,
but we did not perform such an analysis because we aimed to
study the deteriorating ischemic stroke by stratifying patients
into the 4 subgroups of the OCSP.
As expected, the prognosis was worse in the D group than the
ND group in TACI, LACI, and POCI. More sophisticated
markers might be needed to predict deterioration in acute
ischemic stroke for future studies. There are some candidates for
the predictable markers. Dávalos and Castillo and their cowork-
ers21,41,42 have indicated that the blood and cerebrospinal fluid
glutamate concentration increases in progressing stroke. In their
neuroimaging recent study, Toni et al43 reported that flow
analysis by transcranial Doppler ultrasonography can predict the
improvement and deterioration of ischemic stroke. Recently
developed diffusion-weighted and perfusion-weighted MRI44
and cerebral blood flow analysis with single-photon emission
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CT45 or xenon-enhanced CT46 will be useful in the study of
deteriorating ischemic stroke as well.
In conclusion, the frequency of deterioration in acute
ischemic stroke significantly differed among the OCSP sub-
groups, and it worsened the prognosis. Some factors could
predict deterioration: early CT findings in TACI, large-artery
atherosclerosis in TACI and POCI, and stroke severity in
LACI. Future research to find more sophisticated markers
appears to be needed.
Acknowledgments
We would like to thank Drs Hirohiko Murakami, Kenji Koshimizu,
Masatomi Ikusaka, Yuko Shimizu, Mutsumi Iijima, Mika Ueda,
Yuko Sakamoto, and Hiromi Suzuki for their clinical assistance.
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