Pada awalnya, sistem klasifikasi stroke diderivasi dari temuan autopsi yang dikaitkan dengan klinis pasien. Seiring dengan berkembangnya modalitas imaging & investigasi vaskular, klasifikasi stroke yang pada awalnya menitikberatkan pada sindroma klinis beralih menjadi suatu proses decision-making berdasarkan data klinis-radiologis-laboratoris. Menariknya lagi, proporsi subtipe stroke ini pun berubah, sesuai sistem & kriteria yang digunakan... Hmmm, bagaimana dengan klasifikasi dan proporsi tipe stroke di Asia?

1. Ischemic Stroke Subclassification
An Asian Viewpoint
Ersifa Fatimah
PPDS Neurologi FK UNAIR – RS Dr Soetomo
Surabaya | 2016

2. • Characteristics of stroke in
Asian populations
• Review of previous ischemic
stroke classification systems
• Stroke subtyping and related
issues in Asians
Highlights
2

3. Introduction
• Etiologies of ischemic stroke are diverse.
• Appropriate classification of ischemic stroke subtypes is critical for guiding treatment
decisions, determining the prognosis, proper assessment in clinical trials.
• Advances in neuroimaging  improved understanding of the mechanisms of ischemic
stroke  individualized treatment strategies in accord with the particular stroke
pathophysiology
• Proportions of stroke subtypes are well-known to differ based on race or ethnicity +
different prevalence of certain risk factors
• Most of the previous classification systems were developed in Western countries and
based on Caucasian patients
3

4. Diagram of the three-step model of acute diagnostics
C. Warlow, J. van Gijn, M. Dennis, et al. (eds). Which arterial territory is involved?
Using arterial and brain anatomy to develop a clinically based method of
subclassification, in Stroke: Practical Management, 3rd edition. 2007 : Blackwell
4

5. Stroke diagnostic algorithm
5
Toni, Danilo; Sacco, Ralph L; Brainin,
Michael; Mohr, JP. Classifcation of
Ischemic Stroke. In Stroke:
Pathophysiology, Diagnosis, and
Management, 5th edition. Mohr, Wolf,
Grotta, et al (eds). 2011. Elsevier:
Philadelphia

6. Various classification systems are applied to the subtypes of ischemic stroke…
National Institute for Neurological Disordes and Blindness (NINDB), 1958
Harvard Cooperative Stroke Registry, 1978
Stroke Data Bank, 1988
Oxfordshire Community Stroke Project (Bamford), 1991
Trial of ORG 10172 in Acute Stroke Treatment (TOAST), 1993
Stop-Stroke Study TOAST (SSS-TOAST)
Causative Classification System (CCS), 2003
ASCO, 2009
Chinese ischemic stroke classification (CISS), 2011
6

7. Oxfordshire / Bamford classification
Sindr. Definition
TACI At time of maximum deficit, all of:
• Hemiplegia or severe hemiparesis contralateral to thecerebral lesion
• Hemianopia contralateral to the cerebral lesion
• New disturbance of higher cerebral function (e.g.dysphasia, visuospatial disturbance)
+/– sensory deficit contralateral to the cerebral lesion
PACI At time of maximum deficit, any of:
• Motor/sensory deficit + hemianopia
• Motor/sensory deficit + new higher cerebral dysfunction
• New higher cerebral dysfunction + hemianopia
• Pure motor/sensory deficit less extensive than for lacunar syndromes (e.g. monoparesis)
• New higher cerebral dysfunction alone (e.g. aphasia)
When more than one type of deficit is present, they must all reflect damage in the same cerebral hemisphere.
LACI Definition
• Maximum deficit from a single vascular event
• No visual field deficit
• No new disturbance of higher cerebral function
• No signs of brainstem disturbance*
Categories: Pure motor stroke, Pure sensory stroke, Ataxic hemiparesis (including dysarthria–clumsy hand, syndrome and homolateral ataxia and
crural paresis), Sensorimotor stroke
To be acceptable as a pure motor, sensory or sensorimotor stroke, the relevant deficit must involve at least two out of three areas of the face, arm
and leg, and, with particular reference to the arm, should involve the whole limb and not just the hand.
*Some brainstem syndromes may be caused by lacunar
infarcts.
POCI At time of maximum deficit, any of:
• Ipsilateral cranial nerve (III–XII) palsy (single or multiple) with contralateral motor and/or sensory deficit
• Bilateral motor and/or sensory deficit
• Disorder of conjugate eye movement (horizontal or vertical)
• Cerebellar dysfunction without ipsilateral long tract deficit (as seen in ataxic hemiparesis)
• Isolated hemianopia or cortical blindness
Note that disorders of higher cerebral function (e.g. aphasia, agnosias) may be present in addition to the above features if the posterior cerebral
artery territory is involved. 7

8. TOAST Classification
Clinical Radiological Other
Large-artery
Atherosclerosis
Signs of lesion in cortex (aphasia,
apraxia, neglect), subcortex,
cerebellum, or brainstem
−CT/MRI shows lesion >1.5 cm in cortex,
subcortex, cerebellum, or brainstem
compatible with the symptoms.
−CT scan negative when performed shortly
after onset
Color duplex images of
precerebral arteries shows
stenosis ≥50% or occlusion in
symptomatic major intracranial/
extracranial artery
Cardio-embolic Signs of lesion in cortex (aphasia,
apraxia, neglect), subcortex,
cerebellum, or brainstem
−CT/MRI shows lesion >1.5 cm in cortex,
subcortex, cerebellum, or brainstem
compatible with the symptoms.
−CT scan negative when performed shortly
after onset
ECG/TEE confirm high risk /
medium high risk of cardio-
embolic source
Small-vessel
disease
Clinical signs of a lacunar syndrome
(pure motor, pure sensory, sensori-
motor, atactic hemiparesis, or
dysarthria-clumsy hand syndrome)
−CT/MRI shows lacunar infarction (lesion
<1.5 cm) compatible with the symptoms.
−CT scan negative when performed shortly
after onset
No large vessel disease or cardio-
embolic disease identified in
color duplex images of
precerebral arteries or in
ECG/TEE
Other determined Other abnormality on tests
Undetermined 1. Two or more causes identified
2. Negative evaluation
3. Incomplete evaluation
High risk of cardio-embolic source: mechanical heart valve, mitral stenosis + AF, AF, left atrial thrombus, recent myocardial infarction (<4 weeks), left ventricular thrombus,
dilated cardiomyopathy, akinetic left ventricular segment, atrial myxoma, infectious endocarditis.
Medium high risk of cardio-embolic source: mitral stenosis without AF, atrial septum aneurysm, patent foramen ovale, atrial flutter, nonbacterial thrombotic endocarditis,
congestive heart failure, hypokinetic left ventricular segment, myocardial infarction (>4 weeks, <6 months).
Plaque formations >4 mm in aorta ascendens have been added to the list of cardio-embolic sources.
Adams et al., 1993 | Fure at al., 2005
8

9. Stroke classification systems from Western countries
9Kim, Bum Joon; Kim, Jong S. Ischemic Stroke Subtype Classification: An Asian Viewpoint. Journal of Stroke 2014;16(1):8-17

10. Stroke classification systems from Asian countries
The classification systems suggested by Asian investigators share similar concerns in the definition of
ischemic stroke subtypes
1) lesion size limitations should not be strictly applied for small-vessel occlusion
2) the degree of stenosis of atherosclerotic vessels should not be limiting in determining large artery
disease subtypes
10Kim, Bum Joon; Kim, Jong S. Ischemic Stroke Subtype Classification: An Asian Viewpoint. Journal of Stroke 2014;16(1):8-17

11. Characteristics of major etiologic classification systems for ischemic stroke
Chen, et al. Classifying Ischemic Stroke, from TOAST to CISS. CNS Neuroscience & Therapeutics 18 (2012)452–456 11

12. 12
Qualifications for good classification systems

13. Current classification system may not be well
suited to Asian patients?
A classification system more specific to the Asian
population needs to be developed?
1. the proportions and relative importance of stroke subtypes are well
known to differ with race and ethnicity
2. the relative distribution of intracranial, extracranial, and coronary
atherosclerosis may differ between Asians and Caucasians.
3. specific stroke etiologies should be considered in certain stroke
populations due to the presence of genetic differences between
populations
13

14. Stroke subtypes by racial and ethnic groups
*Data from southern Californians (Modifed from Bang et al.), †Data from South Koreans
14
Bang, 2016

15. Comparison of ischemic stroke subtypes in Western and Asian countries
Data from Germany (ESPro), UK (SLESS), China, Japan (Takashima Stroke Registry), Pakistan (Aga Khan University Stroke Database),
and Korea (Korean Stroke Registry)
Note:
• During the last decade, the relative
prevalence of ischemic stroke subtypes
changed:
• cardioembolism increased, and
• small-vessel occlusion decreased.
• These changes were observed in Korea, as
well as in other Asian countries.
• This phenomenon may in part be related to
improved blood pressure control in the
region.
15
Kim, Bum Joon; Kim, Jong S. Ischemic Stroke Subtype Classification: An Asian Viewpoint. Journal of Stroke 2014;16(1):8-17

16. The clinical features and epidemiological data related to stroke in Asians
are different from those in Caucasians.
Asians Non-Asians
Cardioembolism most common (25–30%) cause of ischemic
stroke in Western
Atherosclerotic up to 25–65% of strokes in Asian
Small-vessel
disease
prevalence is higher in Asians, ~50% of ischemic
strokes in Asians
~20% of those in Caucasian patients
Stroke burden disproportionately high in East Asia, Africa, and
South America
Almost 2/3 of the deaths worldwide due to
stroke occur in Asian countries
Ischemic heart
burden
higher in the Middle East, North America,
Australia, and much of Europe
Intracranial
atherosclerosis
high in Asians, causing 30–50% of strokes cause of only 8–10% of strokes in North
America
ECAS >> ICAS
Genetic moyamoya disease (MMD) is higher in Asians
(RNF213 mutation)
sickle cell disease can cause stenosis in
cerebral vessels, and can result in stroke in
blacks
16

17. Symptomatic vessel and atherosclerotic stenosis
in decreasing order of frequency (n = 151)
(Pakistan)
Location of symptomatic atherosclerosis
in 1000 patients. (Korean)
Multiple indicates multiple vessels; p, proximal; d, distal.
Khan, Maria; Rasheed, Asif; Hashmi, Saman; et al.
Stroke radiology and distinguishing characteristics
of intracranial atherosclerotic disease in native
South Asian Pakistanis. International Journal of
Stroke, June 2012
Kim, Jong S.; Nah, Hyun-Wook; Park, Sea Mi; et al. Risk Factors and
Stroke Mechanisms in Atherosclerotic Stroke, Intracranial Compared
With Extracranial and Anterior Compared With Posterior Circulation
Disease. Stroke. 2012;43:3313-3318
17

18. Characteristics of Patients With
Intracranial Atherosclerosis & Extracranial Atherosclerosis
18Kim, Jong S.; Nah, Hyun-Wook; Park, Sea Mi; et al. Risk Factors and Stroke Mechanisms in Atherosclerotic Stroke, Intracranial Compared With Extracranial
and Anterior Compared With Posterior Circulation Disease. Stroke. 2012;43:3313-3318

19. Stroke Mechanisms Associated With Each Symptomatic Vessel (n=925*)
Correlation of stroke mechanisms with increasing
degree of atherosclerotic stenosis (P=0.002).
Advanced stenosis increases haemodynamic strokes
and major cortical embolisms.
19Khan et al, 2012
Kim et al, 2012

20. • The vast majority of Asian patients with ischemic
stroke are classified as having disease of large or
small cerebral arteries.
• The relatively low frequency of intracranial
atherosclerosis in Western countries  little
attention in stroke classification systems
– Patients with intracranial atherosclerosis are often
classified as having cryptogenic embolism  recent
high-resolution MRI & pathological studies have
revealed the presence of intracranial arterial plaques
in these patients.
– Patients with a milder degree of intracranial stenosis
or large and deep infarcts are likely to be classified as
having other cryptogenic causes.
• Prevalence of small vessel occlusion in Asia may be
artifactually elevated due to misclassification of
stroke subtypes.
20

21. Atherosclerotic subtype
Intracranial Extracranial
• Differences in clinical & neuroimaging features, risk factors, vessel wall pathology, and treatment strategies
• Less frequent occurring in both systems
can be caused by diverse conditions: MMD, dissection,
vasculitis, RCVS
Risk factor: metabolic syndrome, nonatherosclerotic conditions
Mainly caused by atherosclerosis
Others (rare): carotid dissection, fibromuscular
dysplasia, Takayasu arteritis, radiation arteritis
Risk factors: older age, male gender, hyperlipidemia
Mechanism: branch occlusive disease/ local branch occlusion,
artery-to-artery embolism, impaired clearance of emboli,
hemodynamic impairment, in situ thrombosis, or combinations
Causes stroke by artery-to-artery embolism 
pathologic and imaging markers of vulnerable carotid
plaque have been well investigated
Branch occlusive disease (intracranial plaques occluding
perforating arteries) often show a mild degree of stenosis and
are misclassified as having lacunar stroke or other cryptogenic
stroke
Lacunar subtype
Deep microbleeds (red type) Leukoaraiosis (white type)
• Different optimal treatment strategies
• Different risk factors
more common in Asians
associated with intracranial hemorrhage
as well as ischemic stroke
may be caused by silent, acute lacunar infarcts
21

22. Gao, S., Wang, Y., Xu, A., Li, Y. and Wanng, D. (2011) 'Chinese ischemic stroke subclassifcation', Frontiers in Neurology, vol. 2, no. 6, pp. 1-5.
• Branch or perforator occlusion is
unique to ICAS patients.
• Branch occlusion is usually associated
with milder atherosclerosis than are
other mechanisms.
• Even in patients with no apparent
stenosis on neuroimaging studies, a
small plaque on the vessel wall can still
cause a single subcortical infarction
(SSI).
22

23. Single Subcortical Infarct vs Small Subcortical Infarct
Large Vessel vs Small Vessel
• Recent studies have shown that single subcortical infarction (SSI) or
brainstem infarcts frequently are caused by
1) branch occlusion associated with parental artery atherosclerotic plaque
2) arteriosclerotic proximal small-vessel disease.
• High prevalence of ICAS in Asia  a large portion of SSIs is likely to be
caused by parental artery atherosclerotic disease.
Orifices of perforating arteries can be obstructed even if the degree of
parental artery stenosis is less than 50%.
Prevalence of SSI associated with ICAS, as detected by MRA: 16.9%-35% in
Asia
• Small atherosclerotic plaque undetectable by conventional MRA has been
observed on high-resolution MRI  proportion of SSIs caused by parental
artery atherosclerosis may be much higher than previously suspected
23

24. Cardioembolic subtype
• AF may not always be the cause of stroke in AF patients.
• One-sixth of strokes in AF patients were reported to be unrelated to AF 
recurrent strokes despite receiving adequate anticoagulation treatment
with warfarin.
• Prevalence of micro- and macroangiopathy is higher in Asians than in
Caucasians, more Asian patients with AF are classified as having
undetermined etiology with two or more cause.
24

25. Advances in Diagnostic Techniques
• Px should not be classified as having atherosclerotic subtype simply because they have stenotic lesions on relevant
proximal vessels
• Visualize wall pathology: atherosclerosis vs non-atherosclerosis (moyamoya, dissection, vasculitis)
• Demonstrating interval changes of basal collaterals and luminal stenosis (esp in moyamoya)
High-resolution MRI
• Predict the risk of stroke
• Cardiac imaging biomarkers as an approach for differentiating between cardiogenic vs non-cardiogenic stroke
• Identification of clinical and prognostic characteristics of SSI associated with HR-MRI-identified plaque.
• Identification of clinical and prognostic characteristics of SSI that abuts the parental artery.
• Technical developments to identify plaques in intracranial arteries at reasonable cost.
• MR or molecular imaging to characterize vulnerable intracranial atherosclerosis.
Biomarkers
• Extensive pathogenic workup may paradoxically increase the prevalence of cause-undetermined cases (i.e., cases with
≥2 determined causes)
• Advanced vascular techniques should be applied to patients with milder stenosis for demonstrating vulnerable
plaques, and to those with a relatively healthy risk factor profile in order to preclude non-atherosclerotic stenosis in
which specific treatment may be needed
• Antithrombotic usage could be guided by the findings of cardiac imaging or gradient-echo imaging
Targeted selection and judicious use of the appropriate tests in the workup of stroke
25

26. Stroke subtyping and related issues in Asians
26Bang, Oh Young. Considerations When Subtyping Ischemic Stroke in Asian Patients. J Clin Neurol 2016;12(2):129-136

27. Recommendations
• Need for a more-detailed stroke classification system of stroke
etiology in Asian patients
• Need for the systematic application of advanced diagnostic
tests in the evaluation of stroke etiology in Asian patients
• Continuous efforts are needed to refine the approach applied
for the workup of Asian patients with ischemic stroke.
• Current guidelines do not provide detailed treatment strategies
according to the subclassification of stroke subtype.
• Future studies should investigate different treatment strategies
for the various subclassifications
• Continuous efforts are needed to individualize the treatments
provided to Asian patients with ischemic stroke
27

28. • Bang, Oh Young. Considerations When Subtyping Ischemic Stroke in
Asian Patients. J Clin Neurol 2016;12(2):129-136
• Kim, Bum Joon; Kim, Jong S. Ischemic Stroke Subtype Classification: An
Asian Viewpoint. Journal of Stroke 2014;16(1):8-17
• Kim, Jong S.; Nah, Hyun-Wook; Park, Sea Mi; et al. Risk Factors and Stroke
Mechanisms in Atherosclerotic Stroke, Intracranial Compared With
Extracranial and Anterior Compared With Posterior Circulation Disease.
Stroke. 2012;43:3313-3318
• Khan, Maria; Rasheed, Asif; Hashmi, Saman; et al. Stroke radiology and
distinguishing characteristics of intracranial atherosclerotic disease in
native South Asian Pakistanis. International Journal of Stroke, June 2012
• Gao, S., Wang, Y., Xu, A., Li, Y. and Wanng, D. (2011) 'Chinese ischemic
stroke subclassifcation', Frontiers in Neurology, vol. 2, no. 6, pp. 1-5.
• Chen, et al. Classifying Ischemic Stroke, from TOAST to CISS. CNS
Neuroscience & Therapeutics 18 (2012)452–456
• Toni, Danilo; Sacco, Ralph L; Brainin, Michael; Mohr, JP. Classifcation of
Ischemic Stroke. In Stroke: Pathophysiology, Diagnosis, and Management,
5th edition. Mohr, Wolf, Grotta, et al (eds). 2011. Elsevier: Philadelphia
References
28

29. DISCUSSION
End.
29