Clinical Neurology and Neurosurgery 159 (2017) 93106

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Clinical Neurology and Neurosurgery

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Etiologic classication of ischemic stroke: Where do we stand? MARK

a a,b, a,b
Rzvan Alexandru Radu , Elena Oana Terecoas , Ovidiu Alexandru Bjenaru ,
Cristina Tiua,b
a
Stroke Unit, Department of Neurology, University Emergency Hospital, Bucharest, Romania
b
Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

A R T I C L E I N F O A B S T R A C T

Keywords: Despite major technological advances in ischemic stroke diagnostic techniques, our current understanding of
Ischemic stroke stroke mechanisms and etiology continues to remain unclear in a signicant percent of patients. As a result,
Classication several etiological ischemic stroke classications have emerged during the last two decades but their reliability
Etiology and validity is far from perfect and further world-wide research is needed in order to achieve the so much needed
Stroke subtypes
standard reference language. An ideal ischemic stroke classication should both comprise all underlying
Causative
Phenotypic
pathologies that could potentially concur to an index event and emphasize the most likely etiological and pa-
thophysiological mechanism. Currently available approaches to ischemic stroke classication are either phe-
notypic or causative in nature, a multitude of criteria being published by dierent authors. Phenotypic classi-
cations are targeted towards describing the concurring underlying pathologies, without highlighting the most
probable ischemic stroke etiology, while causative classications focus on establishing the most likely cause,
neglecting other associated diseases. A judicious use of this two dierent concepts might improve clinical re-
search as well as daily clinical practice.

1. Introduction
Stroke is nowadays one of the major global health problems, com-
prising 75.2% of deaths and 81.0% of stroke-related disability adjusted
life years lost in developing countries [1]. Up to 87% of the global
burden of stroke is attributed to ischemic stroke, which is a hetero-
geneous disorder with more than 100 pathologies implicated in its
pathogenesis [2]. Therefore, a reliable and precise etiologic classica-
tion of this disease is highly important for both daily clinical practice
and research purposes [35]. Currently available approaches to is-
chemic stroke classication are either causative or phenotypic in
nature, several criteria being published by dierent authors [3]. This
paper aims to review currently used etiological classication systems
and to emphasize the importance of a reliable stroke classication
system.
2. Methods
A systematic literature review was done using PubMed to identify
studies and papers published in English between 1st of January 1990
and 1st of January 2017, using the keywords: ischemic stroke,
classication system, etiological classication. Papers were con-
sidered for inclusion based on relevance of title and abstract and were
excluded if the papers didnt t the topic of interest. References cited in
relevant papers were also examined and included if deemed important.
3. Discussion
3.1. History
Etiologic subgroups of ischemic stroke were rst described in 1958
by the National Institute for Neurological Disorders and Blindness
Report on cerebrovascular diseases. Ischemic stroke etiological sub-
groups were at that time designated thrombosis with atherosclerosis,
cerebral embolism, other causes and cerebral infarction of un-
determined origin. The main goal of this initial report was stated by
Milikan as follows: Our ultimate objectives are to obtain greater
clarity of thinking [in regard to cerebrovascular diseases], to compose a
generally acceptable classication, to establish reliable criteria for di-
agnosis [6]. Until the early 1970s ischemic stroke classication was
mainly based on clinical grounds and autopsy studies. The 1970s were
marked by the introduction of computerized brain tomography, the
more frequent use of catheter angiography and by the well known de-
scription of lacunar syndromes by Miller Fischer [79]. The scarce
available data of various clinical ndings in dierent subtypes of stroke
prompted a group of authors led by J.P. Mohr and L.R. Caplan to

Corresponding author at: Department of Neurology, University Emergency Hospital Bucharest, 169 Independentei Street, Sector 5, 050098, Bucharest, Romania.
E-mail address: oana_ter@yahoo.com (E.O. Terecoas).

http://dx.doi.org/10.1016/j.clineuro.2017.05.019
Received 15 March 2017; Received in revised form 6 May 2017; Accepted 18 May 2017
Available online 24 May 2017
0303-8467/ 2017 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
R.A. Radu et al.
develop the Harvard Cooperative Stroke Registry. The Harvard Registry
was the rst prospective computer based registry on any medical con-
dition. Patients with ischemic stroke were classied in three subgroups:
large artery thrombosis, lacunar infarcts and embolism [10,11].
In the meantime, 17 years after the initial NINDB communication,
Milikan referring to ischemic stroke subtypes emphasized a perennial
truth: It continues to be evident that in such a complex set of clinical-
pathophysiological phenomena some standard reference language or
set of denitions should be used, or the literature of investigation will
be uninterpretable [12].
The explosive growth of interest and knowledge about stroke was
driven by the introduction of echocardiography, ambulatory cardiac
rhythm monitoring, B-mode, continuous wave and pulsed-wave
Doppler technology, as well as by high-energy bidirectional pulsed-
Doppler systems for intracranial ultrasound, which were all available in
the late 1980s [13]. The Stroke Data Bank Registry and later on, the
TOAST project (Trial of ORG 10172 in Acute Ischemic Stroke) included
the information achieved through these investigations in the criteria
used for the etiologic classication of ischemic stroke [14,15].
Nowadays, novel and rened imaging data, as well as prolonged
rhythm monitoring techniques provide a vast amount of potential nd-
ings implicated in stroke etiology. With the more frequent implementa-
tion of international registries and wide-scale population studies, the need
for reliable and comprehensive classication systems emerged. This led to
the implementation of the updated TOAST classication (SSS-TOAST),
the Causative Classication System (CCS) and of a comprehensive phe-
notypic ischemic stroke classication (ASCOD) [1618]. Dierent etio-
logical classication systems are listed in Table 1.
3.2. Key concepts in stroke classication systems
3.2.1. Reliability and validity of classication systems
The subject of stroke classications systems cannot be thoroughly
approached without explaining the importance of reliability and va-
lidity. Reliability is the extent to which an experiment, test or mea-
suring procedure yields the same results on repeated trials while va-
lidity is usually dened as the degree to which a research measures
what it intends to measure [19].
The reliability of an ischemic stroke classication system refers to the
reproducible classication of an index ischemic stroke by the same and by
dierent examiners. It is thus, mainly dened by its interrater agreement
(inter observer agreement) which is measured in any situation in which
two or more observers evaluate the same thing [19]. The result is ex-
pressed as the kappa () coecient, which is derived from the dierence
between the observed agreement compared to the agreement expected by
chance alone [20]. There are no strict benchmarks for interpreting va-
lues, a value of 0 usually indicating agreement equivalent to chance,
while a value of 1 indicates perfect agreement. Kappa values between
0.61 and 0.8 are a measure for substantial interrater agreement while
values above 0.81 are considered to show almost perfect agreement [21].
Assessment of the reliability of a classication system is a suitable
Table 1
Ischemic stroke classication systems.
National Institute for Neurological Disorders and Blindness (NINDB), 1958 [6]
Harvard Cooperative Stroke Registry, 1978 [10]
Stroke Data Bank, 1988 [113]
Trial of ORG 10172 in Acute Stroke Treatment (TOAST), 1993 [15]
Baltimore Washington, 1995 [26]
Stop-Stroke Study TOAST (SSS-TOAST), 2005 [46]
Modied-TOAST by Han et al., 2007 [77]
Causative Classication System (CCS), 2007 [16]
ASCO, 2009[25]
Chinese ischemic stroke classication (CISS), 2011 [29]
ASCOD, 2013 [2]
SPARKLE, 2014 [61]
Clinical Neurology and Neurosurgery 159 (2017) 93106
measure to evaluate the message communicated between clinicians and
researchers world-wide and an important determinant in the conception
of clinical trials. Improvement of the reliability of a classication system
from 0.5 to 0.8 might reduce the sample size of a clinical study by around
40% [22]. A classication system might be reliable if it yields the same
results, irrespective of their validity.
Validity is examined by three separate points criterion, construct
and content. Criterion validity is measured with sensitivity, specicity
and positive predictive value and implies a comparison with a gold
standard [23]. However stroke research lacks a gold standard for
etiological diagnosis since there is a declining interest in autopsy stu-
dies [24]. Thus, most classication criteria rely on current diagnostic
technologies and clinical patterns. Even with the use of modern ancil-
lary tests and imaging techniques it is sometimes still debatable whe-
ther the mechanism underlying an ischemic stroke was embolic,
atherothrombotic or hemodynamic. Construct validity is determined by
comparing new classication systems with the old approved ones.
Content validity measures the extent to which an instrument of measure
includes all relevant dimensions of what it intends to measure [23].
3.2.2. Phenotypic versus causative classications
Two main categories of classications are currently being used for
establishing the etiology of ischemic strokes [3]. Phenotypic classi-
cations record all abnormal test ndings, stratify them based on certain
evidence grades without weighting towards the most likely cause. A
phenotypic classication will assign a degree of probability for every
possible stroke etiology. This feature makes phenotypic classications
like ASCOD [2], ASCO [25], CCS [16] and Baltimore-Washington [26]
ideal for large scale epidemiologic and genetic studies, as well as for
ischemic stroke registries [27].
Causative classication systems assign patients with ischemic stroke
in a single category based on available clinical, epidemiological and
diagnostic data. These classications usually rely on a set of criteria
constructed with the help of an estimated risk of stroke attributed to
dierent conditions in large population based studies. Thus, patients
are classied in mutually exclusive categories, thereby reducing the
number of subtypes. However, causality is not easily demonstrated
[28]. Examples of causative systems include: TOAST [15], CCS [16] and
CISS [29]. An overview of the most used ischemic stroke classication
systems is presented in Table 2.
Etiology of ischemic stroke is often multifactorial and therefore an
ideal ischemic stroke classication should both comprise all underlying
pathologies that could potentially concur to an index event and em-
phasize the most likely etiological and pathophysiological mechanism.
Phenotypic classications are targeted towards describing the con-
curring underlying pathologies, without highlighting the most probable
etiology, while causative classications focus on establishing the most
likely cause in a given patient, usually neglecting other associated
diseases. A judicious use of this two dierent concepts might improve
clinical research as well as daily clinical practice.
3.3. Main classication systems
3.3.1. TOAST classication
The TOAST classication is the most widely used system for es-
tablishing ischemic stroke etiology. It was implemented in 1993 by
Adams et al. in order to be used in the Trial of Org 10172 in Acute
Stroke Treatment [15]. Although this trial was negative [30], the
TOAST classication was further used for a large number of epide-
miologic [5], intervention [30], risk factor assessment [31,32] and
prognosis [33] studies for both stroke and transient ischemic attacks
[34]. Furthermore, important ischemic stroke risk factors [35], early
and long term recurrence [4] as well as survival [35] were all found to
dier between TOAST subtypes.
Being fairly simple to use, the TOAST classication provides the
basic skeleton for ischemic stroke classication for clinicians and
94
 Table 2
Overview of etiologic classication systems of ischemic stroke [2,15,16,25,29,46,61,77].

Classication Classication type Stroke groups Evidence grades Inter-rater Advantages Disadvantages
R.A. Radu et al.

agreement

TOAST Causative (1) Large artery atherosclerosis
(2) Cardioembolism
(3) Small vessel occlusion
(4) Other determined etiology
(5) Undetermined etiology
Two or more causes
Negative evaluation
Incomplete evaluation
Probable Moderate Widely used Reliability and validity inuenced by clinical
Possible Easy to use in clinical practice expertise of the adjudicator
Evidence grades frequently neglected
Overestimates the undetermined group
Low reliability for minor strokes

SSS TOAST Causative (1) Large artery atherosclerosis Evident Substantial/ Improved reliability and updated criteria as Not widely used
(2) Cardio-aortic embolism Probable Excellent compared to TOAST Complicated classication scheme
(3) Small artery occlusion Possible Clear algorithm for evidence grades assessment Dicult to use in clinical practice
(4) Other causes Reduces the no. of cases classied as undetermined
(5) Undetermined causes Denes cryptogenic embolism as a separate entity
(a) Unknown
Cryptogenic embolism
Other cryptogenic
Incomplete evaluation
(b) Unclassied

CCS Causative and Same as SSS TOAST Evident Substantial/ Same as for SSS-TOAST, and Same as SSS-TOAST, and
phenotypic Probable Excellent Computerized web-based algorithm Internet requirements
Possible Excellent reliability and validity
Provides phenotypic details

95
ASCO Phenotypic (1) Atherothrombosis (A) 0: Disease absent Substantial/ Comprehensive criteria Complicated classication scheme
(2) Small vessel disease (S) 1: Potentially causal Excellent Minimal and maximum work-up clearly dened Does not emphasize the underlying etiology of the
(3) Cardiac pathology (C) 2: Causal link Provides an overview of all pathologies potentially index stroke
(4) Other causes (O) uncertain involved in stroke pathogenesis Dicult to use in clinical practice
3: Causal link Suitable for clinical studies and registries
unlikely Good validity
9: Insucient work-
up

ASCOD Phenotypic (1) Atherothrombosis (A) 0: Disease absent Substantial/ Same as ASCO, and Same as ASCO
(2) Small vessel disease (S) 1: Potentially causal Excellent Updated criteria
(3) Cardiac pathology (C) 2: Causal link Denes arterial dissection as a stand-alone etiology
(4) Other causes (O) uncertain Minimal and maximal work-up incorporated in
(5) Dissection (D) 3: Causal link evidence grades
unlikely
9: Insucient work-
up

SPARKLE Causative (1) Large artery disease
(2) Cardioembolic
(3) Small vessel disease
(4) Other rare or unusual
etiologies
(5) Undetermined etiologies
Unknown etiology
Incomplete evaluation
Evident Excellent Comprehensive criteria Not widely used
Probable Improved criteria for large vessel disease Not extensively studied in clinical studies
Possible Requires carotid plaques measurement, thus oering
better overview of the cardiovascular risk
Reduces the no. of cases classied as undetermined

CISS Causative (1) Large artery atherosclerosis
Aortic arch atherosclerosis
I/E artery atherosclerosis
(2) Cardiogenic stroke
NA Excellent Well studied in Asian population
Denes underlying mechanism of large artery
atherosclerosis related strokes
Overestimates strokes attributed to large artery
atherosclerosis
Questionable validity in non-Asian population
Criteria for large artery atherosclerosis
(continued on next page)
Clinical Neurology and Neurosurgery 159 (2017) 93106
R.A. Radu et al. Clinical Neurology and Neurosurgery 159 (2017) 93106

investigators alike. It is the most used classication system worldwide

signicantly dierent from other classications

but many criticisms were raised regarding its reliability and validity
[24,27].
Despite the high reliability reported in the initial publication, the
overall inter rater agreement for the TOAST system is now regarded as
moderate [36]. However, reliability varies between subtypes, being
high for atherosclerosis and cardioembolism ( = 0.80) but low for
small vessel disease ( = 0.53) and strokes of undetermined cause
( = 0.40) [36].
Reliability and validity were also shown to vary with the clinical
Disadvantages

expertise of the adjudicator and with stroke severity, agreement being

Same as CISS

usually lower for minor strokes. This might partially explain the above
described dierences in agreement [37]. Diagnostic accuracy and re-
liability for small vessel disease related infarcts is lowered by the strict
criteria which restrict the classication process to lesions smaller than
15 mm and clinical features of lacunar syndromes. The 15 mm cut-o
point was traditionally considered to be the upper size limit of lacunar
infarcts, according to CT studies. However, MRI studies have shown
that in the acute phase infarcts can go up to 20 mm on axial sections
and therefore a strict size criterion is not valid [38]. Moreover, several
Well studied in Asian population

studies have emphasized the limits of clinical lacunar syndromes in

predicting small vessel disease related infarcts [39,40]. In a study re-
ported by Potter et al., 23% of patients with a cortical syndrome had an
acute lacunar infarct, whereas 16% of patients with a lacunar syndrome
had an acute cortical infarct [39]. These ndings indicate that without
magnetic resonance imaging the diagnosis of small vessel disease will
unlikely be precise [41] and clinicians might overinate the un-
Advantages

determined cause group by including here ischemic lesions > 15 mm

that do not t other categories [42].
The strict criteria for small vessel disease and the need to identify a
mechanism might complicate the classication of subcortical infarcts
even further. Studies in Asian patients have recently shown that branch
artery occlusion associated with parental artery atherosclerotic plaques
agreement
Inter-rater

(without hemodynamic signicance) frequently causes single sub-

Excellent

cortical infarcts that may be radiologically indistinguishable from

lacunes [43]. Beside the subcortical infarcts, the undetermined group
might be also overinated with the frequent (4557%) detection of
moderate-risk cardioembolic sources by transesophageal echocardio-
Evidence grades

graphy [44,45]. Thus, many patients might be unreasonably assigned to

the undetermined category due to two identied causes [3,27].
Another drawback of using the TOAST system is that in the clinical
setting the work up is frequently stopped if one etiology is identied,
NA

many patients being classied with low level of condence (possible).

More than two causes identied
AT with signicant stenosis of a

This can lead to overlooked etiologies and misguided treatment options.

(4) Other determined etiology
(3) Penetrating artery disease

Various modied TOAST classications (SSS-TOAST [46], CCS

(1) Atherothrombosis (AT)
(5) Undetermined etiology

(5) Undetermined etiology

Uncertain determination

[16]) have partially updated the classication criteria and solved the
(3) Small artery disease

Incomplete evaluation
Inadequate evaluation

above mentioned problems but the complexity of the algorithms and

(2) Cardioembolism
large artery (ASLA)
(4) Other etiology

the web-based requirements still impede the current use of these sys-
Unknown cause
Multiple causes
Stroke groups

tems. This emphasizes the convenience and the simplicity of the ori-
ginal TOAST system, which are probably the most important qualities
of this widely used classication.

3.3.2. Modied TOAST classications

3.3.2.1. SSS-TOAST and CCS. The SSS-TOAST classication was the
rst published update of the TOAST classication. Its major aim was to
Classication type

improve reliability and update specic TOAST criteria according to

recent clinical and technological advances [46].
Causative

This classication is composed of the same ve major stroke cate-

gories of the TOAST classication but for each causative category the
SSS-TOAST assigns three evidence grades: evident, probable or
KOREAN TOAST

possible. Evidence grades were abstracted between evident and pos-

Table 2 (continued)

sible by using an arbitrary 2% annual or one-time primary stroke risk

Classication

threshold [46].
In order to improve reliability, the threshold size for small vessel
disease associated infarcts was increased from < 15 mm to < 20 mm,
acknowledging the fact that acute infarction can be seen in subcortical

96
R.A. Radu et al.
Table 3
Criteria for classifying large artery atherosclerosis related strokes in dierent classication systems [2,15,16,25,29,46,61,77].
Classication Evidence grades
TOAST Probable
Clinical ndings, neuroimaging data and
results of diagnostic studies consistent with
LAA and other etiologies have been excluded.
(1) Clinical and brain imaging ndings of
signicant (more than 50%) stenosis or
occlusion of a major brain artery, presumably
due to atherosclerosis.
(2) A history of intermittent claudication, TIAs
in the same vascular territory, a carotid bruit
or diminished pulses helps support the clinical
diagnosis.
(3) Cortical or cerebellar lesions and brain
stem or subcortical hemispheric
infarcts > 1.5 cm in diameter on CT or MRI
are considered to be of potential LAA origin.
SSS TOAST Evident
(1) Occlusive or stenotic (50% diameter
reduction) vascular disease judged to be due to
atherosclerosis in the clinically relevant I/E
arteries; and
(2) Absence of acute infarction in vascular
territories other than the stenotic or occluded
artery.
CCS Evident
(1) Occlusive or stenotic (50% diameter
reduction or < 50% diameter reduction with
plaque ulceration or thrombosis) vascular
disease judged to be caused by atherosclerosis
in the clinically relevant I/E arteries; and
(2) Absence of acute infarction in vascular
territories other than the stenotic or occluded
artery.
ASCO A1 (Denitely a potential cause of stroke)
(1) Atherosclerotic stenosis 7099% in an I/E
artery supplying the ischemic eld diagnosed
by level A or B evidence; or
(2) Atherosclerotic stenosis < 70% in an I/E
artery supplying the ischemic eld with
attached luminal thrombus diagnosed by level
A or B evidence; or
(3) Mobile thrombus in the aortic arch; or
(4) Occlusion with imaging evidence of
atherosclerosis in an I/E artery supplying the
ischemic eld.
ASCOD A1 (Potentially causal)
(1) Ipsilateral atherosclerotic stenosis between
50 and 99% in an I/E artery supplying the
ischemic eld; or
(2) Ipsilateral atherosclerotic stenosis < 50%
in an I/E artery with an endoluminal thrombus
supplying the ischemic eld; or
(3) Mobile thrombus in the aortic arch; or
(4) Ipsilateral arterial occlusion in an I/E
artery with evidence of underlying
atherosclerotic plaque supplying the ischemic
eld
SPARKLE Evident
(1) Ipsilateral internal carotid or intracranial
stenosis 50%; or
(2) TPA 1.19 cm2 with absence of evidence
of acute infarction in vascular territories other
than the symptomatic vascular territory
(3) Microemboli detection on continuous
transcranial Doppler monitoring
(4) Subclavian steal syndrome on carotid
Doppler ultrasound
Possible
Clinical ndings, neuroimaging data suggestive
for LAA but other studies are not done.
Probable
(1) Prior history of one or more TMBs, TIAs or
stroke from the territory of index artery aected
by atherosclerosis within the last month; or
(2) Evidence of near-occlusive stenosis or
nonchronic occlusion judged to be due to
atherosclerosis in the clinically relevant I/E
arteries (except for the vertebral arteries); or
(3) Ipsilateral and unilateral internal watershed
infarctions or multiple, temporally separate,
infarctions exclusively within the territory of the
aected artery.
Probable
Same as SSS TOAST
A2 (Causality uncertain)
(1) Atherosclerotic stenosis 7099% in an I/E
artery supplying the ischemic eld diagnosed by
level C evidence; or
(2) Atherosclerotic stenosis < 70% in an I/E
artery supplying the ischemic eld with attached
luminal thrombus diagnosed by level C evidence;
or
(3) Aortic arch plaques > 4 mm in thickness
without a mobile component.
A2 (Causal link uncertain)
(1) Ipsilateral atherosclerotic stenosis 3050% in
I/E artery supplying the ischemic eld; or
(2) Aortic plaque 4 mm without a mobile
lesion
Probable
(1) Presence of another evident cause of stroke,
other than LAD
(2) Presence of signicant carotid and
intracranial atherosclerosis ipsilateral to the
vascular territory generating stroke symptoms,
with conrmation of stroke signs through the
neurological assessment
(3) Past history of TIA or amaurosis fugax
ipsilateral to the carotid or intracranial vascular
territory having signicant stenosis
97
Clinical Neurology and Neurosurgery 159 (2017) 93106
Possible
(1) Presence of an atherosclerotic plaque protruding into
the lumen and causing mild stenosis (< 50%) in a
clinically relevant I/E artery and prior history of 2
TMBs, TIAs or strokes from the territory of index artery
aected by atherosclerosis, at least one event within the
last month; or
(2) Evidence for evident LAA in the absence of complete
diagnostic investigation for other mechanisms
Possible
(1) Presence of an atherosclerotic plaque protruding into
the lumen and causing mild stenosis (< 50%) in the
absence of any detectable plaque ulceration or thrombosis
in a clinically relevant I/E artery and history of 2 TMBs,
TIAs or stroke from the territory of index artery aected
by atherosclerosis, at least one event within the last
month; or
(2) Evidence for evident LAA in the absence of complete
diagnostic investigation for other mechanisms
A3 (Unlikely a direct cause of stroke but disease
present)
(1) Presence of carotid or vertebral artery plaque without
stenosis; or
(2) Aortic arch plaque < 4 mm; or
(3) Stenosis (any degree) in a brain artery, not supplying
the infarct area (e.g. contralateral side or opposite
circulation); or
(4) History of myocardial infarction or coronary
revascularization or peripheral arterial disease.
A3 (Causal link is unlikely, but the disease is present)
(1) Plaque (stenosis < 30%) in an I/E artery, ipsilateral to
the infarct area; or
(2) Aortic plaque < 4 mm without mobile thrombus; or
(3) Stenosis (any degree) or occlusion in a cerebral artery
not supplying the infarct area (e.g. contralateral side or
opposite
circulation); or
(4) History of myocardial infarction, coronary
revascularization or peripheral arterial disease; or
(5) Ipsi- or bilateral atherosclerotic stenosis 5099% with
bihemispheric MR-DWI lesion
Possible
(1) Presence of carotid atherosclerosis causing
stenosis < 50%, or
(2) Presence of 0.12 cm2 TPA < 1.19 cm2 indicating
lower-risk carotid atherosclerotic lesions
(3) Presence of any possible cause of stroke/TIA not
related with symptom onset or presenting stroke/TIA
(continued on next page)
R.A. Radu et al.
Table 3 (continued)
Classication Evidence grades
CISS Aortic arch atherosclerosis
(1) Acute multiple infarcts, especially
involving bilateral anterior and/or anterior
and posterior circulations;
(2) No evidence of atherosclerosis of I/E large
arteries (vulnerable plaques or stenosis 50%
or occlusion);
(3) No evidence of potential cause of
cardiogenic stroke;
(4) No evidence of other etiologies that can
cause multifocal acute ischemic infarcts such
as vasculitidies, hemostatic disturbances, and
tumorous embolism;
(5) Evidence of signicant aortic arch
atherosclerosis (aortic plaques > 4 mm and/or
aortic thrombi, detected by HR-MRI/MRA
and/or TEE).
KOREAN Atherothrombosis
TOAST
(1) Imaging evidence of atherosclerosis of an
I/E artery relevant to the patients symptoms
and signs; and
(2) One or more of the following evidences of
systemic atherosclerosis: (a) documented
atherosclerosis in one or more I/E arteries
other than the clinically relevant arteries, (b)
aortic atheroma demonstrated by TEE, (c)
angiographically documented coronary artery
occlusive disease, (d) angiographically
documented (PAOD); and
(3) Other possible causes of stroke have been
excluded.
LAA = large artery atherosclerosis; TIAs = transient ischemic attacks; TMBs = transient monocular blindness; TPA = total plaque area; TEE = transesophageal echocardiography;
PAOD = peripheral artery occlusive disease; I/E = intracranial or extracranial.
areas on diusion weighted imaging without fullling criteria for any
other etiology [47]. As already mentioned, serial imaging studies sug-
gest that acute diusion weighted imaging overestimate the nal in-
farct volume [48]. A comparison of the criteria for small vessel disease
and large artery atherosclerosis related strokes in dierent classication
systems is presented in Tables 3 and 4.
One major change of the SSS-TOAST with respect to the original
TOAST classication is that protruding arterial atheroma causing less
than 50% stenosis is regarded as a possible source of large artery
atherosclerosis related stroke provided that it is associated with re-
current clinical events and there is no evidence for other stroke me-
chanisms. Criteria dening medium and high risk cardioembolic
sources were also revised, chronic myocardial infarction and congestive
heart failure with low ejection fraction being regarded in SSS-TOAST as
high-risk sources of cerebral embolism. Atrial utter, bioprosthetic
cardiac valves and nonbacterial thrombotic endocarditis were also
listed as high risk sources of ischemic stroke, while mitral valve pro-
lapse and cardiac wall motion abnormalities were completely removed
from the original TOAST list. Another novelty of the SSS-TOAST clas-
sication is the denition of a distinct subtype of undetermined stroke
termed cryptogenic embolism.
Although this algorithm lowered the number of strokes included in
the undetermined group to 4% and the interrater agreement of the
classication was substantially improved ( = 0.78), the complicated
system impeded the wide use of SSS-TOAST. As a consequence, the
complex algorithm was computerized and the web-based variant was
named the Causative Classication System (CCS) [16]. CCS is an in-
ternet based questionnaire-style classication in which clinically re-
levant and ancillary testing data entry is performed in 5 steps. A prin-
table summary page displays both causative and phenotypic details
about stroke subtype [16].
Clinical Neurology and Neurosurgery 159 (2017) 93106
Intra- and extracranial large arteries
atherosclerosis
(1) Any distribution of acute infarcts (except
isolated infarct in the territory of one
penetrating artery), with evidence of
atherosclerosis involving I/E large arteries
(vulnerable plaques or stenosis 50%) that
supply the area of infarction;
(2) Concerning isolated penetrating artery
territory infarct, the following should also be
included in LAA: evidence of atherosclerotic
plaque (detected by HR-MRI) or any degree of
stenosis in the parent artery (detected by TCD,
MRA, CTA, or DSA);
(3) No evidence of potential cardiac-origin
embolic cause;
(4) Other possible causes have also been
excluded.
Atherothrombosis with signicant stenosis of
a large artery (ASLA)
(1) Fulllment of criteria for
Atherothrombosis; and
(2) Either a signicant stenosis 50% or
occlusion of the relevant major brain artery
(carotid, vertebral, basilar arteries, or proximal
segments of the anterior, middle and posterior
cerebral arteries)
CCS comprises few subtle changes of the initial SSS-TOAST classi-
cation. Most importantly, protruding arterial atheroma causing less
than 50% stenosis, regarded in SSS-TOAST as a possible source of large
artery disease stroke if associated with recurrent clinical events, is
considered in CCS criteria for evident large artery atherosclerosis if
accompanied by signs of plaques ulceration and thrombosis [16,46].
Prior to the publication of the original CCS classication, Goldstein
et al. managed to improve the reliability of the original TOAST classi-
cation system from 0.42 to 0.64 [36,49] to 0.75 by also using a
computer-based algorithm. However this improvement was largely at-
tributed to the inclusion of patients with concurrent multiple me-
chanisms in the undetermined group [50]. On the contrary, the CCS
computer-based algorithm classies patients into specic etiologic
subgroups without expanding the undetermined category, which ac-
counts for only 46% of all cases [16].
3.3.2.2. The Spanish Classication system (GEECV/SEN). GEECV/SEN is
the classication system used by the Spanish Society of Neurology
Study Group for Cerebrovascular Diseases. GEECV/SEN is a causative
classication system that resembles TOAST and is easy and feasible to
use. GEECV/SEN criteria classify strokes as atherothrombotic if either
related to a stenosis of more than 50% in a corresponding large extra- or
intracranial artery or if related to carotid plaques or a stenosis of less
than < 50% in a corresponding large artery in the presence of at least 2
predened vascular risk factors. Criteria for small artery disease,
cardioembolic and undetermined strokes are similar to TOAST [51].
3.3.2.3. The SPARKLE classication. The SPARKLE classication was
published in 2014 and is a modied TOAST classication system. The
major aim of the initial study group was to improve criteria for large
vessel disease subtyping. Classication systems like TOAST and SSS-
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R.A. Radu et al. Clinical Neurology and Neurosurgery 159 (2017) 93106

Table 4
Criteria for classifying small vessel disease related strokes in dierent classication systems [2,15,16,25,29,46,61,77].

Classication Evidence grades

TOAST Probable Possible

Clinical ndings, neuroimaging data, results of diagnostic Clinical ndings, neuroimaging data
studies consistent with small vessel disease and other suggest specic subtypes but other studies
etiologies have been excluded. are not done.
(1) Traditional clinical lacunar syndrome with no
evidence of cortical dysfunction. Diabetes and
hypertension are supportive.
(2) Normal CT/MRI examination or relevant brain stem
or a subcortical hemispheric lesion a diameter of less than
1.5 cm.
(3) Absent cardiac sources of embolism. Exclusion of a
stenosis of > 50% in a ipsilateral major artery.
SSS TOAST Evident Probable Possible
Imaging evidence of a single clinically relevant acute The presence of stereotypic lacunar TIAs (1) Presenting with a classical lacunar syndrome in
infarction less than 20 mm in greatest diameter within the within the past week. the absence of imaging that is sensitive enough to
penetrating arteries, in the absence of any other detect small infarctions; or
pathology in the parent artery at the site of the origin of (2) Evidence for evident small artery occlusion in the
the penetrating artery. absence of complete diagnostic investigation for
Clinical syndrome is not taken into consideration. other mechanisms
CCS Evident Probable Possible
Same as SSS-TOAST Same as SSS-TOAST or the presence of a Same as SSS-TOAST
classical lacunar syndrome.
ASCO S1 (potentially causal) S2 (causal link is uncertain) S3 (causal link is unlikely, but the disease is
present)
Association of: (1) Single, deep branch artery stroke; or Leukoaraiosis on MRI (or CT), and/or microbleeds
(1) Small, deep infarct with diameter < 15 mm on MRI (2) Clinical syndrome suggestive of deep on MRI, and/or dilatation of perivascular spaces on
(or CT) in the territory corresponding to symptoms; and branch artery stroke with no MRI/CT MRI (or CT), and/or one or several lacunar infarcts
either: evidence of stroke (silent or old) in territories dierent from the index
(2) One or several old lacunar infarcts in territories stroke
dierent from the index stroke; or
(3) Leukoaraiosis on MRI (or CT), microbleeds on MRI,
dilatation of the perivascular spaces on MRI (or CT); or
(4) Recent repeated similar TIAs, when they preceded the
brain infarct by 1 month or less and attributable to the
same territory as the subsequent brain infarction
ASCOD S1 (potentially causal) S2 (causal link is uncertain) S3 (causal link is unlikely, but the disease is
present)
Same as ASCO Same as ASCO Same as ASCO
SPARKLE Evident Probable Possible
(1) Medical history and physical examination suggesting (1) Typical lacunar syndrome; and (1) Clinical evidence of a lacunar syndrome with
presence of a lacunar syndrome; and (2) Presence of another evident cause of normal brain imaging; and
(2) CT or MRI conrms deep brain infarction of a stroke with a mechanism of disease that (2) Presence of another possible cause of stroke/TIA
diameter 2 cm. cannot explain the presenting symptoms unrelated with presenting stroke/TIA in terms of
Clinical syndrome is taken into consideration. and signs time to symptom onset and mechanism of disease
CISS Evidence grades not applicable
(1) Acute isolated infarct in clinically relevant territory of
one penetrating artery, regardless of the size of infarct;
and
(2) No evidence of atherosclerotic plaque (detected by
HR-MRI) or any degree of stenosis in the parent artery
(detected by TCD, MRA, CTA, or DSA); and
(3) Other plausible causes excluded.
KOREAN-TOAST Evidence grades not applicable
(1) A single ischemic lesion occurring in a single
perforating arterial territory. Strict size criterion not
given but suggested to be usually smaller than 2 cm; and
(2) Normal angiographic studies of the relevant arteries.
Clinical syndrome is not taken into consideration.
A patient with a small artery disease-type brain lesion and a
relevant arterial stenosis or occlusion is classied into
Atherothrombosis if the patient has one or more evidences
of systemic atherosclerosis, but into Stroke of undetermined
etiology of uncertain determination if no evidence of
systemic atherosclerosis is found.

TIAs = transient ischemic attacks; CT = Computed tomography; MRI = Magnetic resonance imaging;TCD = Transcranial Doppler;MRA = Magnetic resonance imaging angiography;
CTA = Computed tomography angiography; DSA = Digital substraction angiography.

TOAST require more than 50% stenosis in the ipsilateral artery in order
to attribute an ischemic stroke to large artery atherosclerosis. However,
recent clinical data on atherosclerotic disease, as well as the often
encountered clinical acumen, challenge this hypothesis. As a result, the
SPARKLE system requires assessment of carotid plaque burden (through
total plaque area measurement) and continuous transcranial Doppler
monitoring for microemboli detection for classifying stroke in patients
with < 50% ipsilateral stenosis of relevant cerebral arteries [52].
Total plaque area is dened as the sum of the cross-sectional areas
of all plaques measured in a longitudinal view in the common, internal

99
R.A. Radu et al.
or external carotid arteries on both sides [53,54]. A total plaque
area > 1.19 cm2 was found to be associated with a 19.5% greater
5 year risk of stroke, death or myocardial infarction [55] after adjust-
ment for traditional coronary risk factors. These ndings, initially
published by Spence et al., were later replicated in dierent populations
[56,57]. Total plaque area can also be increased in patients
without > 50% stenosis of the cervical arteries. This counterintuitive
nding can be elegantly explained by the initial compensatory en-
largement of the atherosclerotic artery described by Glagov et al. in
1987 [58].
Traditional cardiovascular risk factors used for cardiovascular risk
prediction do not adequately explain carotid plaque burden [59]. The
concept of total plaque area is expected to revolutionize preventive
cardiovascular medicine since Spence et al. found that a high Fra-
mingham Risk Score identied only 32% of patients who would ex-
perience cardiovascular events, whereas 77% of such events occurred
among patients in the top quartile of total plaque area (3.4 times higher
risk of stroke, death or myocardial infarction over 5 years) [60]. As a
consequence, the incorporation of carotid plaque measurement in a
stroke classication system might lead to better awareness and treat-
ment of atherosclerosis.
The initial reported intra-rater reliability was excellent and the in-
terrater reliability was substantial. When compared to the CCS classi-
cation, the overall agreement was substantial, the major dierences
being observed in the assignment of large artery atherosclerosis, car-
dioembolism and strokes of undetermined cause. The SPARKLE system
assigned more patients in the large artery disease and cardioembolic
subgroups as compared with CCS [61]. However further studies are
needed to evaluate the SPARKLE system in dierent populations.
3.3.3. Stroke Classications in the Asian populations
The incidence and prevalence of the dierent cardiac, arterial, he-
modynamic or systemic disorders which may underlie the emergence of
an ischemic stroke vary among dierent populations. Classication
systems have to be used world-wide, so it is of major importance to take
into account the innate distribution of the dierent stroke-causing
diseases in dierent populations [42,62].
Ischemic stroke subtype distribution varies in populations of dif-
ferent races and ethnicities because of the asymmetric prevalence of
vascular risk factors as a result of dierent life-styles and intrinsic ge-
netic clustering [6366]. In Western countries cardio-embolism is re-
garded as the most common cause of stroke since the prevalence of
ischemic strokes attributed to large artery disease in these countries is
steadily declining, probably due to the intensive medical management
of atherosclerotic risk factors [5,67]. On the contrary, in Asian popu-
lations large and small vessel diseases are the most frequent causes of
stroke [6870]. Furthermore, intracranial artery disease accounts for
3050% of the ischemic stroke burden in Asia, whereas in North
America it is incriminated in only 810% of cases [71,72]. This dis-
crepancy in etiology might blur the true incidence of dierent ischemic
stroke subtypes in Asian patients when classied with unsuitable cri-
teria.
Considering this propensity for intracranial vessel disease in the
Asian population, an adequate classication system designated to be
used in this part of the world should acknowledge the fact that lacunar
infarctions due to branch occlusion or due to diseases like Moya-Moya,
vasculitis and arterial dissections are much more frequent in Asian
patients than in patients of European ancestry [43,73].
Because of the high prevalence of intracranial atherosclerosis in
Asia, several groups of authors modied the TOAST criteria in order to
improve the detection of relevant intracranial large artery disease and
to reduce strokes wrongly assigned to small vessel disease or with a
deemed undetermined cause. The most important changes introduced
by the rst published papers on this topic concerned the classication
of small subcortical ischemic strokes and strokes due to atherosclerotic
disease. Thus, subcortical strokes of less than 20 mm are attributed to
100
Clinical Neurology and Neurosurgery 159 (2017) 93106
large artery disease and not to small vessel disease if an arterial ste-
nosis, even < 50%, in the parent artery is identied. Strokes are also
attributed to large artery disease in the presence of ipsilateral intra or
extracranial atherosclerosis and when no other cause is identied
[74,75].
3.3.3.1. Korean TOAST. The modied TOAST classication published
by Han et al. [75] in 2007 was termed Korean TOAST [29]. Since
atherosclerosis is presumed to account for the vast majority of strokes in
Asian patients, Han and colleagues decided to include all patients with
evidence of systemic atherosclerotic disease, in the absence of other
possible causes, in a distinct group called atherothrombosis. In this
classication, the patients who meet the TOAST criteria for large artery
atherosclerosis will constitute a subgroup of atherothrombosis called
atherosclerosis with signicant stenosis of large arteries (ASLA) [75].
These changes increase the number of ischemic strokes attributed to
atherothrombosis and decrease the number of strokes classied as
undetermined. However, the widespread use of this classication
system in dierent study populations is questionable, since the
rationale for the creation of this wide group called
atherothrombosis relies on a study in which a small number of
Asian patients were classied according to TOAST criteria and further
on screened for systemic atherosclerosis and cardiovascular events
[76]. Although in the original study in which the Korean TOAST
classication was implemented the interrater agreement was excellent
( = 0.82), the value for the TOAST classication was also
signicantly higher than previously reported ( = 0.79) [77].
3.3.3.2. CISS. CISS is a two step classication system that intends to
dene both the etiological as well as the pathophysiological ischemic
stroke mechanism. Similar to the Korean authors that implemented the
previously discussed modied TOAST classication, the CISS authors
redened the large artery atherosclerosis criteria and created a new
concept termed penetrating artery disease instead of small vessel
disease [29].
Both the CISS and the Korean TOAST criteria attribute a large
number of strokes to atherothrombosis. The rationale that underlies
these modied criteria is the available evidence suggesting that the
degree of stenosis is not the sole predictor of stroke recurrence, the total
plaque burden [78] and plaque stability [79] being also relevant.
However, the importance of unstable plaques in stroke medicine is still
a matter of debate. The concept of vulnerable plaques was rst in-
troduced in the setting of coronary syndromes where ruptured plaques
with thin brous caps were shown to be often associated with acute
infarctions [80,81]. Nevertheless, the importance of this concept for the
cerebral circulation is debatable, since the pathophysiological me-
chanism of stroke related to large artery disease is largely dierent from
that determining myocardial infarction. Even if its tempting to assume
that isolated, non-stenosing unstable plaques carry a higher risk of
stroke as compared to the stable ones, clear evidence derived from large
population-based studies is scarce. Future results of the currently on-
going studies on this subject (CAPIAS, CARE-II, PARISK) will probably
oer valuable insight about the risk of stroke in this clinical setting,
thus clarifying the veracity of CISS and Korean TOAST classication
criteria [8284].
3.3.4. The A-S-C-O and A-S-C-O-D classications
In 2009 Amarenco et al. published the A-S-C-O phenotypic classi-
cation [25]. A-S-C-O stands for: atherosclerosis; small vessel disease;
cardiac sources; other causes. This classication describes all con-
current pathologies that can potentially lead to an ischemic stroke in a
given patient with the ultimate goal to answer the broad question: why
could this patient suer a stroke? and not why did this patient suer
the index stroke?.
Although fairly complex at rst sight, the A-S-C-O system actually
resembles daily medical reasoning. It ts perfectly into the current
R.A. Radu et al.
clinical practice by gradually answering the questions that every stroke
neurologist should raise in front of every patient: Which diagnostic tests
should I use for accurate identication of stroke etiology? Which are the
underlying patients diseases that could lead to an ischemic stroke?
Which is potentially causal for the index stroke? Which is his future risk
of stroke? Which is the best secondary prevention strategy?
This phenotypic classication was revised in 2013 and termed A-S-
C-O-D [2]. The new system introduced arterial dissection as a stand
alone category (due to the high prevalence of this nding in young
patients with ischemic stroke) and simplied the methods of classi-
cation by incorporating the levels of diagnostic evidence into the grades
of the disease. The threshold of signicance for carotid artery stenosis
and intracranial artery stenosis was decreased from 70% to 50%.
A major advantage of the ASCOD grading system over the TOAST
classication is the very low proportion of ischemic strokes in which no
ASCOD evidence grades of 1, 2 or 3 can be identied [85]. As a con-
sequence, the proportion of strokes of undetermined etiology despite
extensive work-up signicantly diminishes. Even if in many cases the
causality between the identied diseases in each category and the index
stroke cannot be certainly proven (grades 2 and 3), the ASCOD phe-
notype gives an overview of all potential factors that might concur to
future ischemic cerebrovascular events, thus oering valuable in-
formation for guiding treatment strategies.
Using ASCOD criteria a large overlap between the 3 main etiologies
(cardiac disease, large artery disease and small vessel disease) was
identied. Therefore, from a practical point of view identied pathol-
ogies should all be considered when managing the patient regardless of
which is judged to be causal for the index stroke. Atherosclerotic dis-
ease, even if not causally related, is identied in 90% of patients,
highlighting the importance of meticulous atherosclerotic risk factor
control in all ischemic stroke patients [17].
Although more complicated to use in daily clinical practice than the
TOAST classication, the A-S-C-O-D system is a useful tool in the era of
national registries and large epidemiological studies. This rigorous
classication algorithm can be of valuable use in the process of se-
lecting patients with specic types of cerebrovascular diseases. For
example, regardless of the presumed etiology of an ischemic stroke all
patients with concurrent relevant small vessel disease will be classied
at least S3. Since all these patients can be selected for inclusion in an
epidemiological study focusing on risk factors for small vessel disease,
the number of patients selected from a hospital-based or national reg-
istry will be greatly enhanced. The presence of dierent evidence
grades for each ASCOD category oers important advantages when
studying rare diseases or imaging patterns of special subtypes of is-
chemic stroke in large databases. For example, Schwarzbach et al.
studied DWI patterns in cancer-related strokes by excluding patients
with other competing stroke etiologies, dened as evidence grades 1 or
2 for the A, S, C and D categories [86]. The comprehensive overview
provided by ASCOD phenotyping can also be of major importance in
secondary prevention studies, in which a specic ischemic stroke sub-
type is usually targeted [3,87].
The reported interrater agreement for the ASCO/ASCOD classica-
tions is substantial or excellent. With values of 0.78/0.95 for ather-
osclerosis, 0.79/0.95 for small vessel disease, 0.87/1 for cardiac dis-
ease, the ASCO/ASCOD systems clearly outscore the 0.420.64 global
value of the TOAST classication [36,49,85,88].
3.4. Comparisons between dierent classication systems
The need for a reliable and valid stroke classication system is of
utmost importance for stroke research and clinical practice. As long as
etiologic classication of stroke will be subject to variation in dierent
parts of the world, studies will continue to yield puzzling results, be-
cause correct data interpretation requires a standard language and
standard criteria. The components of focused clinical questions in
modern evidence based medicine are frequently described using the
101
Clinical Neurology and Neurosurgery 159 (2017) 93106
acronym PICO and its various variants, where P stands for population,
I for intervention, C for comparison and O for outcome. Consequently,
without homogenously dened populations of patients with a pro-
blem clinical decision making will unlikely benet from the results of
the vast amount of studies published nowadays [89].
A major goal of all ischemic stroke classication systems developed
after the initial publication of TOAST classication was to minimize the
category of undetermined strokes without lowering the accuracy of
classication for other stroke categories. In TOAST, strokes with more
than one possible cause are grouped together with strokes of unknown
etiology due to incomplete work-up and the ones of unknown etiology
despite extensive evaluation in the broad group of strokes of un-
determined cause, which comprises around 25% of all ischemic strokes.
Since minimal work-up requirements for each TOAST category are not
clearly stated, in daily clinical practice the percentage of strokes of
undetermined etiology will depend on the physicians perseverance to
investigate a patient and on the availability of diagnostic tools.
Phenotypic classications, like ASCO and ASCOD [2,25], lack a
predened undetermined group. Intuitively, any stroke associated
with a phenotype containing one single category graded 9 will be of
undetermined etiology due to incomplete evaluation and phenotypes
with at least two graded 1 categories will designate a stroke of un-
determined etiology due to more than 1 causal mechanism identied. It
is still a matter of debate whether a truly undetermined stroke is sup-
posed to have a phenotype with all 5 ASCOD categories graded 0 or
whether the phenotypes including also grades of 3 should be placed
under the same umbrella.
In SSS-TOAST and CCS, undetermined strokes are dened on the
basis of well established criteria, which are completely dierent from
the original TOAST ones. This change, together with the modied de-
nition for the other stroke categories, led to a decrease of strokes
classied as undetermined to 813% of all ischemic strokes [90]. In
SSS-TOAST and CCS, a distinct category of undetermined stroke is
stroke attributed to cryptogenic embolism, which is probably the rst
ocial designation of the clinical construct published by the CS/ESUS
International Working Group in 2014 and named embolic stroke of
undetermined source (ESUS) [91]. The concept of ESUS is more a me-
chanism oriented denition than a causative one, since embolism is
considered to be the sole stroke mechanism but the emboli can arise
from a multitude of both cardiac and vascular sources.
Occult paroxysmal atrial brillation (AF) is probably the most
commonly suspected ESUS etiology and consequently several studies
addressed this topic over the past years. The rate of AF detection in
patients with strokes of unknown etiology after initial diagnostic eva-
luation varied among dierent studies between 3.2 and 30% depending
on the method and duration of monitoring [92]. However, the denite
causal link between paroxysmal atrial brillation detected during
follow-up and a preceding stroke is still being questioned for several
reasons. First, dierent studies investigating the temporal relationship
between subclinical AF detection and ischemic stroke in patients with
implantable pacemakers and debrillators proved that in only a min-
ority of cases AF occurs in the 30 days preceding stroke onset [9395].
In ASSERT study, subclinical episodes of AF were detected in 35% of
patients who experienced an ischemic stroke or systemic embolism
during follow-up but in only 8% of cases these episodes were detected
in the 30 days preceding the embolic event and other studies showed
similar results [96]. Second, although AF is dened by consensus as an
irregular heart rhythm with specic features, lasting for more than 30 s,
a few studies have also quantied the detection of brief episodes of AF
lasting less than 30 s in stroke patients and reported that more than half
of the AF episodes detected by means of dierent continuous mon-
itoring devices are episodes lasting less than 30 s [9799]. Since the
duration of AF needed for thrombus formation in the left atrial ap-
pendage is much longer, it is questionable whether these brief AF epi-
sodes lasting less than 30 s can be direct determinants of emboli for-
mation or are rather biomarkers for more prolonged AF episodes of
R.A. Radu et al.
Table 5
PFO related criteria in dierent ischemic stroke classication systems [2,15,16,25,29,46,61,77].
PFO PFO + ASA
TOAST Medium-risk CE source
SSS-TOAST Low or uncertain CE Low or uncertain CE source
source
CCS Same as SSS-TOAST Same as SSS-TOAST
ASCO/ASCOD Causal link unlikely (C3) Causal link is uncertain
(C2)
SPARKLE
CISS
Korean-TOAST Medium-risk CE source
CE = cardioembolic; PE = pulmonary embolism; DVT = deep venous thrombosis; ASA = atrial septal aneurysm.
sucient duration to result in cardiogenic embolization [99]. It has also
been hypothesized these subclinical episodes of AF may be indicators of
the emerging concept of atrial cardiopathy, which may be by itself
associated with an increased risk of stroke [100]. Third, the clinical
relevance of very short episodes of AF detected by long term cardiac
rhythm monitoring is further questioned by several studies showing
that brief episodes of AF are fairly common in stroke survivors, irre-
spective of stroke subtype [101].
Another entity that has not encountered a clear place in stroke
classication systems (see Table 5), but is listed among ESUS etiologies,
is PFO. Paradoxical embolism is the main postulated mechanism of PFO
related strokes but in situ thrombosis and propensity for cardiac ar-
rhythmias have also been proposed [102]. The increased availability of
transesophageal echography over the last decade initially generated a
true epidemy of PFO-related strokes, since PFO can be detected in up
to 58% of patients with cryptogenic strokes [103]. Later on, several
PFO characteristics together with clinical and imaging features asso-
ciated with a high risk of thromboembolism have been suggested. In
2012, RoPE investigators proved that risk of stroke recurrence in pa-
tients in which PFO is deemed to be causal is actually very low and
provided a score to help distinguishing between stroke-related and in-
cidental PFO in cryptogenic stroke patients [104]. Since the causal re-
lationship between PFO and stroke is dicult to prove in the majority
of cases, stroke classication systems usually list PFO as a low-risk
cardioembolic source without further comments. ASCOD and SPARKLE
criteria provide more comprehensive approaches to classify ischemic
stroke when PFO is identied but further renement is probably needed
[2,61].
Another pathology considered to potentially underlie an ESUS,
aortic arch atherosclerosis, is dierently approached by currently used
ischemic stroke classications and thus represents a potential source of
disagreement between these systems. Aortic arch disease is not men-
tioned at all in TOAST. In modied TOAST classications (SSS-TOAST
and CCS) and SPARKLE, complex aortic atheroma is regarded as a low-
risk source of cardioembolism because ischemic strokes related to this
etiology share similar clinical and neuroimaging features with strokes
attributable to cardiac sources of embolism, whereas ASCO/ASCOD and
Asian classications list aortic plaques of more than 4 mm as criteria of
large artery atherosclerosis [2,16,46,61,75].
From a practical perspective, the optimal treatment strategy in pa-
tients with ESUS is currently a matter of debate but the soon expected
results of Respect-ESUS [105], Navigate-ESUS [106], Atticus [107] will
probably shed more light into this very important topic. Moreover, if
anticoagulant drugs will prove their superiority over antiplatelets, the
ESUS concept will become of signicant importance in daily clinical
practice and consequently ischemic stroke classications will have to be
modied in order to incorporate this concept as a stand alone stroke
category.
An important argument for the importance of reliability in stroke
research is made by the NINDS SiGN study, the largest study of ischemic
Clinical Neurology and Neurosurgery 159 (2017) 93106
PFO + additional clues of paradoxical embolism PFO + in situ thrombosis
(1) Potentially causal (C1) if concomitant PE or DVT preceding the index Potentially causal (C1)
stroke
(2) Causal link uncertain (C2) if concomitant PE or DVT not preceding
the index stroke
High- risk CE source High- risk CE source
High- risk CE source High- risk CE source
stroke subtyping published so far [108]. The SiGN consortium retro-
spectively classied 16954 patients from 12 U.S. and 11 European
studies using the Causative Classication System. The stroke classi-
cation process was meticulously performed in order to minimize
variability between centers [90,108]. This study underlined the im-
portance of a standardized investigation practice when classifying is-
chemic stroke for study purposes. It identied important dierences in
the distribution of phenotypic and causative subgroups in patients in-
vestigated by variable means (i.e. large artery disease was classied as
evident in 21% of the fully investigated population as opposed to 11%
of those with routine investigations) [90].
Important advances in stroke work-up have been made during the
two decades that followed the initial publication of the TOAST classi-
cation, but the costs associated to ischemic stroke work-up should also
materialize in valid classication systems. A recent study that in-
vestigated the validity of ischemic stroke classications showed that
CCS, TOAST and ASCO systems generate distinct subtypes with dif-
ferent clinical characteristics, all systems providing signicant dis-
crimination for the validation variables tested (90-day survival, NIHSS
score at admission, admission infarct volume) [109]. The area under
curve for 90-days stroke recurrence was higher for CCS than for ASCO
and TOAST (AUC 0.71 vs. 0.66 vs. 0.61), but the tested validation
variables signicantly diered between etiological subtypes for all
three classication systems. Although far from perfect, the CCS classi-
cation might therefore be more suitable for etiological subtype as-
sessment in large stroke clinical trials [109].
The largest analysis of the agreement between the TOAST and CCS
classications was also published by the SiGN consortium and not un-
expectedly (dierent classication criteria) a moderate overall agree-
ment with wide variability in dierent study sites (from 28% to 90%)
was reported. The authors of the study ironically concluded that ba-
sically the two systems classify stroke in dierent categories, but un-
fortunately they are named the same. These ndings should lead to
caution when interpreting comparisons between studies that use dif-
ferent classication criteria [110].
Previous comparisons between TOAST, CCS, and ASCO showed
good overall agreement between all classication systems [111].
However, when comparing categories graded ASCO 1 with corre-
sponding TOAST categories fewer patients were classied as small ar-
tery disease and more as large artery atherosclerosis. Agreement be-
tween categories graded as potentially causal or evident in ASCO and
CCS ranged from good to excellent. CCS assigned fewer patients to the
undetermined group while ASCO better characterized patients classi-
ed as TOAST-undetermined. Another study proved that main mis-
matches in classifying strokes by either TOAST or ASCO/ASCOD cri-
teria were accounted by the fact that the TOAST system classies
strokes in patients with PFO as cardioembolic and strokes in patients
with competing etiologies in the undetermined group [85].
CISS classication system [29] was recently compared with TOAST
in an Asian trial involving mainly minor strokes. Interagreement
102
R.A. Radu et al.
between the two classication systems was only moderate. CISS as-
signed 77% less patients than TOAST in the undetermined group and
79% more patients in the large artery atherosclerosis group [112].
These dierences can be explained by the markedly dierent CISS
criteria for small vessel disease and large artery atherosclerosis as
compared to TOAST. These dierences in classication criteria are of
major importance when interpreting results of clinical trials conducted
in Asian patients and further emphasize the importance of an unique,
reliable and valid ischemic stroke classication system in all major
therapeutic trials.
4. Conclusions
Despite major technological advances in ischemic stroke diagnostic
techniques, our current understanding of stroke mechanisms and
etiology continues to remain unclear in a signicant percent of patients.
Since a plethora of classication systems are nowadays used for is-
chemic stroke subtype assessment, clinicians and researchers should
carefully weigh the advantages and disadvantages of each of them, in
order to choose the most suitable classication for their individual
purposes. Development of modern phenotypic classication systems has
been a major breakthrough during the last decade but their reliability
and validity is far from perfect and further world-wide research is
needed in order to achieve the so much needed standard reference
language.
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