Classifying Ischemic Stroke, From TOAST to CISS

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single institution. A government-sponsored stroke registry wasthen proposed. Derived from the Harvard Stroke Registry, theStroke Data Bank was created and funded by the National In-stitute of Neurological Disease and Stroke [5]. At that time ofpatient enrollment into this Stroke Data Bank, the diagnostictechnology had changed again. Nearly all patients had brainCT scans and many had echocardiography. The introduction

of CT technology allowed more accurate determination of thelocation and the extent of ischemic stroke.

2. The Oxfordshire Community Stroke Project (OCSP) clinicalclassication system was a simple tool. It was based on the clin-ical symptoms alone, or in combination with CT scan ndings[6]. Because of its simplicity, it has been used in routine clini-cal practice, large-scale observational studies and clinical trials.This classication addressed the severity and outcome of thestroke but not the causes [7]. However, OCSP classication hadsome limitations: (1) The site of the brain infarction was notspecic enough for a particular stroke etiology. (2) This classi-cation failed to investigate potential risk factors of stroke. (3)The discrimination between lacunar and small-volume corti-

cal infarcts was not accurate, especially when only the clinicalcriteria was used [8].

TOAST

The purpose of the TOAST classication system was to better cat-egorize stroke patients for the purpose of investigating any po-tential efcacy of the anticoagulant danaparoid for treatment ofvarious types of ischemic strokes [1]. This system was primarily based on clinical features plus any information from neuroimag-ing, echocardiography, neurosonography, and cerebral angiogra-phy. Even though the trial failed to show any efcacy of usingdanaparoid, the TOAST classication system has been used exten-

sively for other purposes, such as identifying new genetic mark-ers and risk factors [9,10]. The TOAST system was composed ofve major subtypes: large artery atherosclerosis (LAA), cardioem- bolism (CE), small artery occlusion (SAO), stroke of other de-termined cause (SOC), and stroke of undetermined cause (SUC;Table 1). SUC was further divided into (1) no cause was founddespite an extensive workup or (2) two or more plausible causeswere found. Compared to the other previously described systems,the TOAST system used more objective criteria for stroke subtyp-ing. It was thought to be a simple, logical, and useful system.It incorporated level of diagnostic certainty into subtype assign-ments, and was validated by independent groups for predicting“hard” stroke outcomes, such as functional dependency or death.Since then, this classication system has been widely used for over2 decades. The TOAST investigators noted that stroke prognosis,risk of recurrence, and choice of management were inuenced byischemic stroke subtypes. However, whether the TOAST criteriawere appropriate for a mechanism-oriented classication systemremained unsettled. It also had several important limitations: (1)SAO was dened by the clinical syndrome and the size of the in-farct ( ≤ 15 mm in diameter). Consequently, a single larger deepinfarct could be classied as SUC rather than a more appropri-ate diagnosis of SAO [14]. (2) TOAST would categorize approx-imately 40% of all strokes into the SUC group, including those

patients with potential multiple etiologies or had incomplete diag-nostic work-up. (3) Some subtype denitions relied only on users’opinion or interpretation. As a result, the TOAST classication sys-tem only had moderate interrater reliability [15–17].

Causative Classication System (CCS)

Because the TOAST classication of acute ischemic stroke wasdependent upon patient’s clinical feature and baseline CT scanndings, which were often unrevealing, there was a need fora better classication of stroke subtypes that would incorpo-rate new technological advances and the levels of diagnostic ev-idences. In the 10 years after the introduction of the TOASTsystem, stroke can be better diagnosed with new neuroimagingtechnology, such as diffusion-weighted magnetic resonance imag-ing (MRI) and magnetic resonance angiography [18]. Differentdiffusion-weighted MRI patterns are associated with specic strokecauses. For example, in a case of acute ischemic stroke in which both symptomatic internal carotid artery stenosis and atrial b-rillations are present, clinicians may use diffusion-weighted MRIto determine the most probable etiological mechanism. Further-more, LAA or CE may suggest if there are multiple lesions in theregion supplied by a clinically relevant artery or bilateral lesions[14].

The CCS project was launched in 2003 by a group of physiciansinterested in developing an evidence-based etiologic classicationscheme for acute ischemic stroke [19,20]. It was a web-basedclassication system based on TOAST, which categorizes ischemicstroke into potentially ve major subtypes (Table 1). It is availablefree for academic use at http://ccs.mgh.harvard.edu. The CCS wasdevised to overcome the major limitations of the TOAST system.The primary goal was to achieve high reliability without inatingthe “unclassied” category. To achieve this goal, the CCS classi-

es stroke based on published evidence, and by integrating resultsof multiple diagnostic stroke evaluation (diffusion-weighted MRI,CT angiography and magnetic resonance angiography, echocar-diography, and Holter monitoring). In this system, if multiple po-tential causes existed, the patient would be assigned to a subtype based on the most likely mechanism. The objective criteria usedin TOAST are updated in the CCS, to allow stratication of cardiacsources of embolism into high- and low-risk groups, with refer-ence to an objective 2% primary stroke risk threshold. The CCSalso revised the conventional denition for lacunes and includedlesions of up to 20 mm in diameter. The “undetermined” categoryin TOAST was broken into several subcategories in the CCS: un-known, incomplete evaluation, unclassied stroke (more than oneetiology), and cryptogenic embolism (angiographic evidence of anabrupt cutoff in an otherwise normal-looking artery or subsequentcomplete recanalization of a previously occluded artery). Makingcryptogenic embolism into a distinct category may give researchersthe opportunity to study new embolic sources in a more renedway [11].

The current CCS Version 2.0 provides both causative and phe-notypic stroke subtypes. It relies on ve sources of data: clinicalevaluation, brain imaging, extracranial and intracranial vascularsurvey, heart evaluations, and work-up for uncommon causes ofstroke. In addition, the author has made several revisions and

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T a b l e 1

C h a r a c t e r i s t i c s o f m a j o r e t i o l o g i c c l a s s i c a t i o n s y s t e m s f o r i s c h e m i c s t r o k e [ 1 1 , 1 2

, 1 3 ]

T O A S T

C C S

A - S - C - O

C I S S

P u b l i c a t i o n y e a r

1 9 9 3

2 0 0 7

2 0 0 9

2 0 1 1

T y p e o f s y s t e m

C a u s a t i v e

C a u s a t i v e a n d p h e n o t y p i c

P h e n o t y p i c

C a u s a t i v e

M a j o r s u b t y p e s

1 . L a r g e a r t e r y

1 . S u p r a - a o r t i c l a r g e a r t e r y a t h e r o s c l e r o s i s

1 . A t h e r o s c l e r o s i s

1 . L a r g e a r t e r y

a t h e r o s c l e r o s i s

2 . C a r d i o e m b o l i s m

2 . C a r d i o - a o r t i c e m b o l i s m

2 . C a r d i o e m b o l i s m

2 . C a r d i o g e n i c

s t r o k e

3 . S m a l l v e s s e l o c c l u s i o n

3 . S m a l l a r t e r y o c c l u s i o n

3 . S m a l l v e s s e l d i s e a s e

3 . P e n e t r a t i n g a r t e r y d i s e a s e

4 . O t h e r d e t e r m i n e d e t i o l o g y

4 . O t h e r c a u s e s

4 . O t h e r c a u s e s

4 . O t h e r e t i o l o g i e s

5 . U n d e t e r m i n e d e t i o l o g y

5 . U n d e t e r m i n e d c a u s e s

5 . U n d e t e r m i n e d e t i o l o g y

A d v a n t a g e s

W o r l d w i d e u s e

S i m p l e

, l o g i c a n d e a s y t o u s e

V a l i d a t i o n b y i n d e p e n d e n t g r o u p s

P r e d i c t i n g p r o g n o s i s a n d r i s k o f s t r o k e

r e c u r r e n c e

R u l e s a n d c r i t e r i a b a s e d o n p u b l i s h e d

E v i d e n c e

U p d a t e d c r i t e r i a

t o s t r a t i f y c a r d i o e m b o l i s m

i n t o h i g h - a

n d

l o w - r

i s k g r o u p s

W e b - b

a s e d a u t o

m a t e d v e r s i o n a v a i l a b l e

R e d u c i n g t h e r a t i o o f “ u n d e t e r m i n e d ”

c a t e g o r y

I n t e g r a t i o n o f d i a g n o s t i c e v a l u a t i o n i n t o

t h e l e v e

l o f c o n d e n c e f o r s u b t y p e

a s s i g n m e n t s

C l a r i e d d i a g n o s t i c c r i t e r i a t o i d e n t i f y o r

r u l e o u t a s t r o k e e t i o l o g y

I n t e g r a t i o n o f n o n c a u s a t i v e f a c t o r s i n t o

s u b t y p e a s s i g n m e n t s

I n c o r p o r a t i o n o f t h e e t i o l o g y a n d

u n d e r l y i n g m

e c h a n i s m i n t o s t r o k e

s u b c l a s s i c a t i o n

C r e a t i n g a n e w

s u b t y p e o f P A D

L a r g e a r t e r y a t h e r o s c l e r o s i s f u r t h e r

s u b c l a s s i e d i n t o f o u r c a t e g o r i e s

D i s a d v a n t a g e s

O n l y m o d e r a t e i n t e r - r a t e r r e l i a b i l i t y

O v e r s i z e d “ u n d e t e r m i n e d ” e t i o l o g y

N o t t t o r e c e n t a d v a n c e s i n d i a g n o s t i c

t e c h n o l o g y

D e p e n d i n g o n t h e a v a i l a b i l i t y o f m o d e r n

d i a g n o s t i c t e c h n o l o g y

B a s e d o n e v i d e n c e f r o m d i v e r s e s t u d i e s

A o r t i c a r c h a t h e r o s c l e r o s i s b e l o n g i n g t o

c a r d i o - a

o r t i c e m b o l i s m

F u r t h e r r e l i a b i l i t y a n d v a

l i d i t y d a t a n e e d e d

I n t e r p r e t a t i o n c a u t i o u s

l y w i t h t h e

c o m b i n a t i o n

o f c a u s a t i v e a n d

n o n c a u s a t i v e f a c t o r s

D e p e n d i n g o n t h e c o m p l e t e n e s s o f

d i a g n o s t i c t o o l s

T o o m a n y p h e n o t y p i c s u b t y p e s ( n

= 6 2 5 )

f o r r e s e a r c h s t u d i e s

T o o r e s t r i c t i v e d e n i t i o n t o d i a g n o s e

a t h e r o s c l e r o s i s a n d s m a l l v e s s e l d i s e a s e

L a c k i n g r e l i a b i l i t y a n d v a

l i d i t y d a t a

D e p e n d s o n t h e a v a i l a b i l i t y o f b r a i n

a n d v a s c u l a r i m a g i n g

F u t u r e i m a g i n g t e c h n o l o g y n e e d e d t o

v e r i f y t h e c o n c e p t o f P A D

A S C O

, a t h e r o s c l e r o s i s , s m a l l v e s s e l d i s e a s e , c a r d i a c c a u s e s

, o t h e r u n c o m m o n c a u s e s ; C

C S , C a u s a t i v e C l a s s i c a t i o n o f S t r o k e S y s t e m ; C I S S , C h i n e s e I s c h e m i c S t r o k e S u b c l a s s i c a t i o n ; P A D

, p e n e t r a t i n g

a r t e r y d i s e a s e ; T O A S T

, T r i a l o f O R G

1 0 1 7 2 i n a c u t e s t r o k e t r e a t m e n t .

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clarications to the terms anddenitions in CCS from the feedbackof members and users of the previous version. Evidence showedthat the CCS had good to excellent intrarater and interrater re-liability [21]. However, CCS also had some drawbacks: (1) It was based on the evidence from diverse studies. (2) It depended on theavailability of brain and vascular imaging. (3) The author decidedto include aortic atherosclerosis in the category of CE, contrary to

other classication systems [22].

Atherosclerosis, Small-Vessel Disease, CardiacSource, Other Cause

The A-S-C-O ( A therosclerosis, S mall-vessel disease, C ardiacsource, O ther cause) phenotypic stroke classication system wasproposed by an international group of leading stroke experts [23](Table 1). Unlike the TOAST system, the A-S-C-O system as-signed a level of likelihood to each potential cause and reectedthe most likely etiology without ignoring other unrelated vascularconditions [12]. With the A-S-C-O classication, patients who had

atherosclerotic disease were assigned an A subtype without con-sidering the causality. An atherosclerotic disease denitely relatedto the index stroke was classied as A1, uncertain causality as A2,and atherosclerosis present but unlikely related to the index strokeas A3. In the absence of atherosclerosis the grade was A0, and incase of insufcient work-up the grade was A9. This was the mainconcept of the A-S-C-O classication. The rater should know thedenition of each subtype clearly and every patient would receivea phenotypic score (e.g., A3-S3-C1-O0). This system was designedfor a variety of purposes, such as describing patient demographicsin clinical trials, grouping patients in epidemiological studies, phe-notyping in genetic studies, and classifying patients for therapeuticoptions in clinical practice. For example, if we plan to analyze ge-netic polymorphism or a new risk factor in patients with LAA, we

can take all A1 to A3 cohorts identied by the A-S-C-O system,whereas in TOAST only the small proportion of patients classiedas LAA can be selected.

Compared to TOAST, A-S-C-O is more stringent in its deni-tions of LAA (i.e., A1 in A-S-C-O) and SAO (i.e., S1 in A-S-C-O). To be assigned a A1, the A-S-C-O system requires a crite-ria of > 70% stenosis or < 70% stenosis but with attached lumi-nal thrombus. This criterion would exclude patients with 50–70%stenosis for whom that more aggressive therapy may be of bene-t. To diagnose S1, a deep infarct with a diameter < 15 mm must be present along with the presence of an old lacunar infarct orleukoaraiosis, or recent, repeated, similar transient ischemic at-tacks. Overall, this system classies ischemic strokes into 625 phe-notypic subtypes, integrates features unrelated to the event intostroke subtype assignments, and relies on the availability of brainand vascular imaging studies. A study designed to assess the re-liability and validity of the A-S-C-O system showed that it hadgood-to-excellent agreement with TOAST, and that the A-S-C-O

grade 1 interrater reliability was good to excellent for A1, C1, andO1, but only moderate for S1 [24].

Chinese Ischemic Stroke Subclassication

The principle of the Chinese Ischemic Stroke Subclassication

(CISS) system was conceived at a neurology discussion forum(http://www.rhammer.cn/), where several neurologists discussedthe pathophysiology of SAO and LAA. CISS has two steps. Therst step aims at etiological classication and the second step atfurther classifying the underlying mechanism of ischemic stroke.At the rst step, CISS classied stroke into ve categories basedon the concept of TOAST, but the SAO subtype was renamed aspenetrating artery disease (PAD) [13] (Table 1). PAD was denedas an acute isolated infarct in the clinically relevant territory ofone penetrating artery, regardless of the size of infarct. CISS pro-posed that PAD was caused by atherosclerosis at the proximal seg-ment of the penetrating artery or lipohyalinotic degeneration ofan arteriole. With the advent of new imaging technology, such ashigh resolution magnetic resonance angiography, the wall of thepenetrating artery could be directly visualized and further PADsubclassications have now become possible [25]. In addition,aortic arch atherosclerosis is classied into LAS, which makes itmore consistent with real pathological changes. At the second step,CISS further classies the underling mechanism of ischemic strokefrom intracranial and extracranial LAA into four categories ac-cording to the modern imaging technology: parent artery (plaqueor thrombus) occluding penetrating artery, artery-to-artery embolism, hypoperfusion/ impaired emboli clearance, and multiplemechanisms. Actually, CISS has introduced a classication systemthat considers both etiological and pathophysiological causes. Al-though the reliability and validity of CISS have not been studied, itrepresents an innovative classication system that more faithfully

reects the pathophysiology of stroke.

ConclusionEtiologic classication of stroke is primarily a research tool. Withthe advent of modern diagnostic technologies and the improvedunderstanding of underlying mechanisms of ischemic stroke, newclassication and subclassication systems of stroke need to bereliable, valid, ease to use, evidence-based, and incorporate newinformation as it emerges. A good stroke classication system iskey to select patients for genetic phenotyping, conduct epidemi-ological studies, and make treatment decisions and prognosticpredictions.

Conict of InterestThe authors declare no conict of interest.

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Classifying Ischemic Stroke, From TOAST to CISS