Comparison of the Chinese ischemic stroke subclassification and Trial of Org 10172 in acute stroke treatment systems in minor stroke
Tan et al. BMC Neurology
Comparison of the Chinese ischemic stroke subclassification and Trial of Org 10172 in acute stroke treatment systems in minor stroke
Sha Tan 0 1 2
Lei Zhang 0 2 4
Xiaoyu Chen 0 2 3
Yanqiang Wang 2 5
Yinyao Lin 1 2
Wei Cai 1 2
Yilong Shan 1 2
Wei Qiu 1 2
Xueqiang Hu 1 2
Zhengqi Lu 1 2
0 Equal contributors
1 Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University , No 600 Tianhe Road, Guangzhou City, Guangdong , China
2 Abbreviation: A-A, Artery-to-artery; CE , Cardioembolism; CISS, Chinese ischemic stroke subclassification; CS, Cardiogenic stroke; CTA, Computed tomography angiography; DWI, Diffusion weight imaging; ECG, Echocardiography; END, Early neurological deterioration; HR-MRI, High-resolution brain magnetic resonance imaging; ICAS, Intracranial atherosclerosis; LAA, Large artery atherosclerosis; MES, Microembolic signals; MRA, Magnetic resonance angiography; NIHSS , National institutes of health stroke scale; OE , Other etiologies; PA, Penetrating artery; PAD, Penetrating artery disease; PFO, Patent foramen ovale; SAO, Small artery occlusion; SOE , Stroke of other determined etiologies; SUE, Stroke of undetermined etiology; TCD , Transcranial doppler; TEE, Transesophageal echocardiography; TIA, Transient ischemic attack; TOAST , Trial of Org 10172 in Acute Stroke Treatment; UE , Undetermined etiology
3 Department of Neurology, People's Hospital of Zhongshan City , No 2 Sun Yat-sen East Road, Zhongshan City , China
4 Department of Neurology, The Fifth Affiliated Hospital of Sun Yat-sen University , No 52 Meihuadong Road, Zhuhai City , China
5 Department of Neurology, Affiliated Hospital of Weifang Medical University , No 465 Yuhe Road, Weifang City , China
Background: The underlying causes of minor stroke are difficult to assess. Here, we evaluate the reliability of the Chinese Ischemic Stroke Subclassification (CISS) system in patients with minor stroke, and compare it to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) system. Methods: A total of 320 patients with minor stroke were retrospectively registered and categorized into different subgroups of the CISS and TOAST by two neurologists. Inter- and intra-rater agreement with the two systems were assessed with kappa statistics. Results: The percentage of undetermined etiology (UE) cases in the CISS system was 77.3 % less than that in the TOAST system, which was statistically significant (P < 0.001). The percentage of large artery atherosclerosis (LAA) in the CISS system was 79.7 % more than that in the TOAST system, which was also statistically significant (P < 0.001). The kappa values for inter-examiner agreement were 0.898 (P = 0.031) and 0.732 (P = 0.022) for the CISS and TOAST systems, respectively. The intra-observer reliability indexes were moderate (0.569 for neurologist A, and 0.487 for neurologist B). Conclusions: The CISS and TOAST systems are both reliable in classifying patients with minor stroke. CISS classified more patients into known etiologic categories without sacrificing reliability.
Minor stroke; Diffusion weight imaging; Chinese Ischemic Stroke Subclassification; Trial of Org 10172 in Acute Stroke Treatment; Implications for treatment
Ischemic stroke is a major cause of worldwide
neurological morbidity and mortality. Identifying the cause of
ischemic stroke is of great value for therapeutic choice
and prognostic evaluation [
]. The Trial of Org 10172
in Acute Stroke Treatment (TOAST) system is the most
widely used classification system , but it is of limited
utility in cases of “stroke of undetermined etiology
(SUE)” and has modest inter-examiner reliability [
overcome these issues, modifications to the original
TOAST system have been made. For example, a Korean
group proposed a new classification system for brain
infarctions in 2007, which enriched the definitions of
subtypes of ischemic stroke and proved to have higher
reliability than the previous system [
The Chinese Ischemic Stroke Subclassification (CISS)
system was proposed by Gao et al. in 2011 [
with TOAST, CISS removed small artery occlusions
(SAO), proposed penetrating artery disease, and further
classified the underlying mechanisms of large artery
atherosclerosis. These changes would be beneficial for the
classification of minor stroke which is receiving increased
attention in China. However, the reliability of the CISS
categorization system has not been assessed. This study
aimed to evaluate the reliability of the CISS in patients
with minor stroke and to compare the performance of the
CISS and TOAST systems in these patients.
This research was approved by the ethics committee of
the Third Affiliated Hospital of Sun Yat-sen University
and conforms to the relevant regulatory standards. All
participants involved in this study provided written
The cohort was recruited retrospectively from the
Department of Neurology of The Third Affiliated Hospital
of Sun Yat-Sen University. In total, we screened 3205
consecutive patients with ischemic stroke admitted to
our hospital between January 2008 and August 2013. Of
these, 320 patients fulfilled the inclusion criteria: (a)
onset age ≥18 years, (b) onset time ≤7 days, (c) lesions on
diffusion weight imaging (DWI), and (d) National
Institutes of Health Stroke Scale (NIHSS) score ≤3 on
admission. The inclusion procedure is presented in Fig. 1. All
patients underwent echocardiography (ECG) or 24 h ECG
(94.4 %), high-resolution brain magnetic resonance
imaging (HR-MRI), intracranial magnetic resonance
angiography (MRA), DWI, and extra-cranial vascular imaging.
Risk factors for stroke were also assessed, including
gender, hypertension, diabetes, current cigarette smoking,
coronary heart disease, previous transient ischemic attack
(TIA) or stroke, and peripheral arterial disease.
The subtype classification
Patients were classified into five
etiologic/pathophysiological categories according to the TOAST system: large
artery atherosclerosis (LAA), cardioembolism (CE), SAO,
stroke of other determined etiologies (SOE), and SUE. To
be diagnosed as LAA, patients should have paraclinical
brain imaging findings of either significant (>50 %)
stenosis or occlusion of large arteries, such as the internal
carotid artery, middle cerebral artery, vertebral artery, and
basilar artery, or their major branches, that is presumably
caused by atherosclerosis. Diagnosis of CE requires
paraclinical signs of a source of cardiac embolism. The
category of SAO, which is often labeled as lacunar stroke,
should have one of the traditional clinical lacunar
syndromes and the HR-MRI examination can be normal or
have a relevant lesion with a demonstrated diameter of
less than 1.5 cm. In this category, the potential of LAA
and CE should be eliminated. Patients with either more
than one potential cause or no probable etiology were
classified as stroke of undetermined etiology [
CISS is a two-step system. The first step assigns
patients into 5 etiology-based categories: LAA, cardiogenic
stroke (CS), Penetrating artery disease (PAD), other
etiologies (OE), and undetermined etiology (UE). The
difference is that the CISS system further assigns intra- and
extra-cranial LAA and PAD into categories on the basis
of pathogenesis; something not done in the TOAST
system. The second step is to further classify the underlying
mechanism of ischemic stroke from the intracranial and
extracranial LAA into the parent artery (plaque or
thrombosis) occluding penetrating artery (PA),
artery-toartery (A-A) embolism, hypoperfusion/impaired emboli
clearance, and multiple mechanisms [
]. Acute isolated
infarction located in penetrating artery territory such as
the basal ganglia or the pons is attributable to parent
artery occluding PA, with evidence of plaque or stenosis in
the parent artery. Multiple, scattered lesions in cortical
and subcortical territories of relevant atherosclerotic
vessel are usually in A-A subtypes. The diagnosis could be
confirmed by transcranial doppler (TCD)–microembolic
signals (MES) on TCD as to the single infarct. The
hypoperfusion/impaired emboli clearance refers to the infarcts
located in borderzone areas, usually accompanied with
severely stenosed (>70 %) or occluded vessels. When there
are two or more of the above mechanisms, we consider it
to be multiple mechanisms. CISS also interpreted PAD as
atherosclerosis at the proximal segment of the penetrating
artery or lipohyalinotic degeneration of an arteriole. Two
illustrations of CISS: First, a isolated penetrating artery
infarct is classified in undetermined etiology if there is
evidence of vulnerable plaques or stenosis ≥50 % in ipsilateral
proximal intracranial or extracranial large arteries which
includes carotid artery. Second, any other distribution of
acute infarcts (except isolated infarct in the territory of
one penetrating artery), with evidence of vulnerable
plaques or stenosis ≥ 50 % in carotid artery or vertebral artery
which supply the area of infarction would support the
diagnosis of LAA. The operating procedure is presented
in Fig. 2. Two neurologists classified all of the patients
independently using TOAST and CISS criteria.
Statistical analyses were performed with SPSS 19.0 (SPSS
Inc., Chicago, IL, USA). Quantitative data were expressed
as mean values ± standard deviations (SD) or median values
(interquartile range), qualitative data were described by
relative numbers. Independent proportions were compared
using chi-square or Fisher’s exact tests as appropriate.
Inter- and intra- agreement with the TOAST and CISS
classifications systems were assessed with kappa statistics.
k > 0.80 represented excellent agreement; 0.80 < k < 0.60
represented substantial agreement; 0.60 < k < 0.40
represented moderate agreement; 0.40 < k < 0 represented fair
or poor agreement. The threshold for statistical
significance was set at p < 0.05.
Baseline characteristics of the patients with minor stroke
The clinical features of the patients with minor stroke
are summarized in Table 1. The cohort comprised 203
men (63.4 %) and 117 women (36.6 %). The mean age
was 64 years (range 28–91), the median NIHSS score on
admission was 2 (range 0–3). Of these, 231 (72.2 %) had
hypertension, 127 (39.7 %) had diabetes mellitus, 174
(54.4 %) had dyslipidemia, 29 (9.1 %) had coronary artery
disease, 67 (20.9 %) had previous ischemic stroke
(including TIA), 26 (8.1 %) had peripheral arterial disease,
and 101 (31.5 %) were current smokers.
Etiological subtypes of patients with minor stroke
As shown in Table 2, after classifying the patients with
both the TOAST and CISS systems, we then compared
the two. With CISS, 44.4 % (142/320) of the patients
were classified into LAA, 4.1 % (13/320) into CS, 42.8 %
(137/320) into PAD, 1.9 % (6/320) into OE, and 6.9 %
(22/320) into UE. With TOAST, 24.7 % (79/320) of the
patients were classified into LAA, 4.7 % (15/320) into
CE, 38.4 % (123/320) into SAO, 1.9 % (6/320) into SOE,
and 30.3 % (97/320) into SUE. The CISS system
classified 77.3 % less patients into UE than the TOAST
system, which was statistically significant (P < 0.001).
Moreover, 79.7 % more patients were classified as LAA
in the CISS system than in the TOAST system, which
was also statistically significant.
Reliability of the CISS and TOAST systems
Inter- and intra-reliabilities were measured by
considering percent agreement of the two systems, and by using
the unweighted k statistic. To evaluate the inter-rater
reliability, two experienced neurologists independently
assigned 320 patients to stroke subtypes on the basis of
TOAST/CISS definitions. Intra-rater reliability was
assessed by having the same observers classify the same
320 cases with the two different systems. The kappa
value representing inter-rater agreement in the CISS
system was 0.898 (P < 0.001, Tables 3, 7), and agreement
between the two neurologists occurred in 266 of the 320
patients (83.1 %). While the reliability of the TOAST
classification was 0.732 (P < 0.001, Tables 4 and 7), the
two neurologists agreed on a subtype classification using
the system in 261 of the 320 cases (81.6 %). Using both
systems, observer A arrived at the same diagnosis for
158 of the 320 patients (49.4 %), and the observer B did
this for only 134 (41.9 %). The intra-observer reliability
indexes between TOAST and CISS criteria were 0.569
for neurologist A, and 0.487 for neurologist B (P < 0.001,
Tables 5, 6 and 7).
Minor stroke is receiving an upsurge of attention in
China. The CHANCE study showed that a combination
of clopidogrel with aspirin is superior to aspirin alone
for protecting against subsequent stroke in new TIA and
minor stroke patients [
]. However, this study did not
categorize the patients according to etiology, which is
critical to individualized therapy. As combining the
results of randomized controlled trials with individualized
considerations may have therapeutic benefits, we believe
that it would be beneficial for minor stroke patients to
identify their underlying etiology.
The TOAST system is the most standard etiological
classification system for ischemic stroke. As medical
technology and clinical studies progress, the
pathogenesis of ischemic stroke becomes more concrete. The
CISS system represents a new etiological system for
ischemic stroke [
]. A significant decline in subtypes of
LAA and SVD in stroke/transient ischemic attack has
been found in Western countries like England and
]. However, LAA, especially intracranial
atherosclerosis (ICAS), is more common in Asian societies
]. Furthermore, a high proportion of ICAS patients
who experienced a minor stroke were at high risk of
developing early neurological deterioration (END) [
CISS system, which further classifies the underlying
mechanism of LAA, might therefore be more appropriate for
use with Chinese patients with minor stroke. However,
the reliability of CISS has not been assessed. Here, we
compared the CISS and TOAST systems in patients of
minor stroke and examined reliability scores for them.
CISS Chinese ischemic stroke subclassfication, TOAST trial of Org 10172 in acute stroke treatment, LAA large artery atherosclerosis, CE cardioembolism, CS
cardiogenic stroke, SAO small-artery occlusion, PAD penetrating artery disease, SOE stroke of other etiologies, OE other etiologies, SUE stroke of undetermined
etiology, UE undetermined etiology
@ indicate relative change between two classifications
*P < 0.001
CISS-etiologic category of minor stroke patients
In our study, 320 minor stroke patients were divided
into five primary categories, consistent with the diverse
causes and mechanisms known to underlie strokes.
According to CISS, LAA was the largest subtype, which
may be explained by the high prevalence of ICAS in
]. However, CS was less than 5 % in our
study, which is partly because most cardiac embolisms
cause severe neurological deficits [
] that results in
an NIHSS score of above 3 on admission. Furthermore,
there may have been limitations in our diagnostic tools.
For example, transesophageal echo (TEE) and 30 events
monitor or loop monitor are not routine procedures for
ischemic stroke patients in our hospital.
Distribution of etiology-CISS compared with TOAST
In our study, minor stroke patients were classified into
diverse groups according to the etiology and mechanism
CISS Chinese ischemic stroke subclassfication, LAA large artery atherosclerosis,LAA-A aortic arch atherosclerosis, LAA-1 parent artery (plaque or thrombus) occluding
penetrating artery, LAA-2 artery-to-artery embolism, LAA-3 hypoperfusion/impaired emboli clearance, LAA-4 hypoperfusion/impaired emboli clearance, CS cardiogenic
stroke, PAD penetrating artery disease, PAD-1 lipohyalinotic degeneration of arterioles, PAD-2 atherosclerosis at the proximal segment of the penetrating arteries, OE
other etiologies, UE undetermined etiology
k = 0.898
of the disease. We found mismatches in LAA and UE
with CISS and TOAST. In the TOAST system, most
patients were classified into SAO, followed by UE and
LAA, whereas in CISS, LAA and PAD groups took the
largest proportion. This may reflect some differences in
the definitions of subtypes across the two systems.
In our study, about half of the patients that were
classified into SUE in TOAST were ascribed to LAA in CISS
Table 5 Distribution of CISS and TOAST subtypes by
LAA CE SAO SOE
LAA 77 2 11 0
TOAST trial of Org 10172 in acute stroke treatment, LAA large artery
atherosclerosis, CE cardioembolism, SAO small-artery occlusion, SOE stroke of
other etiologies; SUE, stroke of undetermined etiology
k = 0.732
CISS Chinese ischemic stroke subclassfication, TOAST trial of Org 10172 in acute
stroke treatment, LAA large artery atherosclerosis, LAA-A aortic arch atherosclerosis,
LAA-1 parent artery (plaque or thrombus) occluding penetrating artery, LAA-2
artery-to-artery embolism, LAA-3 hypoperfusion/impaired emboli clearance, LAA-4
hypoperfusion/impaired emboli clearance, CS cardiogenic stroke, PAD penetrating
artery disease, OE other etiologies, UE undetermined etiology, CE cardioembolism,
SAO small-artery occlusion, SOE stroke of other etiologies, SUE stroke of
k = 0.569
(52/97 in Neurologist A’s results, 38/82 in Neurologist
B’s results). TOAST explicitly defines LAA with both
specific stenosis degree of parent artery and size of
lesion. As a result, if no other cause was found, the
following two conditions would be classified as SUE using the
TOAST classification: stenosis degree ≤ 50 % with the
lesion diameter ≥ 1.5 cm; stenosis degree >50 % with the
lesion diameter < 1.5 cm. By contrast, CISS does not
include a restriction for stenosis degree or lesion diameter.
Additionally, more than a quarter of the patients
classified into SUE in TOAST were ascribed to PAD in CISS
(27/97 in Neurologist A’s results, 25/82 in Neurologist
B’s results). To help differentiate from lacunar stroke,
CISS proposed the notion of PAD, as caused by
atherosclerosis at the proximal segment of the penetrating
artery or lipohyalinotic degeneration of an arteriole. The
diagnosis of PAD was established for isolated penetrating
artery territory infarct, when there was no evidence of
atherosclerotic plaque or any degree of stenosis in the
parent artery. The diagnostic procedure ignores the
lesion size and clinical manifestation. Thus, compared
with TOAST, CISS significantly decreased the number of
patients classified as SUE, and might be more useful for
clinicians to assess the etiologies and mechanisms of
patients with minor stroke.
Differences between SAO and LAA were found to be
the second discrepancy between TOAST and CISS, likely
attributable to the different definitions of LAA used by
the two systems. In TOAST, isolated PA territory infarct is
classified into LAA only when both of the following
conditions are included: i) brain imaging findings of either
significant (>50 %) stenosis or occlusion of parent artery; and
ii) the lesion is not smaller than 1.5 cm in diameter. By
contrast, CISS further classifies LAA into four categories
according to the underlying mechanism and emphasizes
the significance of atherosclerotic plaque other than the
lesion size. This means that proof of atherosclerotic
plaque, any degree of stenosis in the parent artery, or new
isolated PA territory infarcts should all be ascribed to
LAA. Indeed, when other possible causes were excluded,
patients with multiple small lesions (diameter <1.5 cm) in
cortical or subcortical regions were attributed to SAO
with the TOAST criteria, but classified into LAA in CISS
if all the lesions were in the territory of the stenosed
artery. In fact, the potential mechanism of this kind of
infarct is artery-to-artery embolism [
], a branch of LAA
with CISS. Therefore, a portion of SAO patients in
TOAST were classified as LAA in CISS.
Inter-rater reliability: CISS compared with TOAST
Both TOAST and CISS were found to be reliable in
our study (inter-rater agreement: k = 0.732 for TOAST,
k = 0.898 for CISS). CISS, which categorized the etiologic
subtypes of minor stroke with excellent inter-examiner
reliability based on assessment of clinical data obtained
through medical record abstraction, showed higher
practical utility. Although the TOAST classification has been
widely used in prospective clinical trials and retrospective
studies, its reliability was not always excellent or stable in
previous studies [
]. By contrast, the high
interexaminer agreement rates of the CISS suggest its potential
utility in stroke research, though it should be noted that
there are still some issues when applying CISS criteria.
Differences in interpretation of medical records were a
leading source of disagreement among examiners, and
discrepant comprehension of subtype definition also
contributed to the instability of CISS.
Generally, k > 0.80 represents excellent agreement;0.80 < k < 0.60 is thought to
be substantial agreement; 0.60 < k < 0.40,moderate agreement; 0.40 < k < 0.20,
fair agreement; and k < 0.20, slight or poor agreement
*P < 0.001
Implications for treatment: CISS Classification
CISS is a more detailed etiologic system for ischemic
stroke than TOAST, which means that it might be more
practical for individualized treatment. As mentioned
before, the underlying mechanism of patients with
lowgrade stenosis and small lesions is artery-to-artery
embolism and/or impaired emboli clearance with CISS. For
them, the root is the instability of plaques or thrombi, so
intensive statin therapy may be beneficial. With regard
to hypoperfusion cases, hypervolemic treatment is
essential. However, we have to acknowledge that whether the
impact of CISS on the schemes of therapy and secondary
prevention could change clinical outcomes is still
uncertain. Large prospective studies may be the only way to
reach a definite conclusion.
Limitations of study
There are some limitations in our research: (a) since we
do not included the patients with moderate and severe
strokes, our conclusions should not be generalized to
the whole population of cerebral infarction; (b) as a
retrospective study, bias is inevitable; (c) the insufficient
diagnostic work-up could affect the accuracy of some
results. For financial reasons, only a subset of patients
took the examination of head computed tomography
angiography (CTA), which is more precise in diagnosis
of vascular stenosis. However, we do use high resolution
MRA to increase the accuracy of the assessment. TCD
emboli-monitoring and TEE are still not carried out in
our hospital. The former is used to detect MES,
especially in patients with a potential cardioembolic source,
which is less common in minor stroke. Besides, a study
with large cohort indicated that MES prevalence was
relatively low in patients with a potential native
cardioembolic source [
]. Therefore, the lack of TCD
embolimonitoring might not have a significant impact on our
results. TEE could identify patent foramen ovale (PFO),
although controversy still surrounds the issue of the
relationship between PFO, paradoxical embolism, and
cryptogenic stroke [
]. Embolic Stroke is more
likely to happen in PFO patients combined with venous
], which was not found in our
objects. It therefore seemed reasonable to exclude the
possibility that lack of TEE might significantly affect our
results. Finally, we note there are some published studies
that share the same insufficient diagnostic work-up with
]. In addition, a continuous heart monitor
study could be required for definitive diagnosis of
paroxysmal atrial fibrillation - a common cause of stroke, but
for now it is difficult to implement because of the
limited medical resource and economic cause.
Our study shows several characteristics of the CISS and
TOAST systems. Despite the lower reliability, TOAST
has the advantage of simplicity, convenience and
proficiency in practice. CISS enriches information about
etiology and pathogenesis. In particular, CISS classifies
more patients of minor stroke into known and precise
etiologic categories, has higher reliability and may be
more conducive to guide individual treatment. However,
CISS requires more detailed examination, which will
have financial implications. It is very important to note
that this study was only conducted with minor stroke
patients with NIHSS ≤3 and the results cannot be
generalized to patients with moderate and severe strokes.
This study was supported by Science and Technology Program of
Guangzhou (Grant number: 2011Y200017).
Availability of data and materials
The individual data collected for each patient in our study cannot be shared in
order to ensure the confidentiality. But the data would be available from the
corresponding author on reasonable request and after local ethical amendment.
ST, LZ, XC: study design, interpretation and manuscript preparation. YW, YL:
clinical data collection. YS: biological indicators collection. XH and WQ: MRI
evaluation, analysis and patients’ diagnosis. WC: statistical analysis. ZL: study
design and supervision. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
This research was approved by the ethics committee of the Third Affiliated
Hospital of Sun Yat-sen University and conforms to the relevant regulatory
standards. All participants involved in this study provided written informed
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