This document discusses the pathophysiology of ischemic stroke. It describes the main mechanisms of ischemic stroke including large artery disease, small artery disease, and cardiac embolism. Large artery disease is mainly caused by thrombosis superimposed on atherosclerosis in major arteries. Atherosclerosis preferentially occurs in bifurcation areas of arteries. Stroke mechanisms in large artery disease include artery-to-artery embolism, in situ atherothrombotic occlusion, hypoperfusion, and branch occlusion. Small artery disease causes lacunar infarctions through lipohyalinosis in small penetrating arteries. Cardiac embolism accounts for 20-25% of ischemic strokes and is mainly caused by atrial fibrillation,

1. PATHOPHYSIOLOGY OF
ISCHEMIC STROKE

2. Introduction
• Stroke is a heterogeneous disorder associated
with diverse pathogenic mechanisms
• Understanding these mechanisms is
important in determining treatment and
prevention strategies in individual patients

3. MECHANISMS OF STROKE

4. Large artery disease
• major cause of cerebral infarction in
developed countries
• main pathology - thrombosis superimposed
on atherosclerosis
• other diseases such as dissection, vasculitis,
and moyamoya disease

5. atherosclerosis
• prone to occur in bifurcation areas - where
blood turbulence is expected to occur
• These areas include the carotid bulb, siphon,
proximal middle cerebral artery (MCA),
proximal vertebral artery, mid-basilar artery,
and proximal posterior cerebral artery (PCA)

6. • ECAS - especially ICA bulb disease, is the most
common form of LAD in Caucasians
• ICAS is more frequent than ECAS in Asian
• Male sex, hyperlipidaemia, and coronary
heart disease are more closely associated with
ECAS
• female sex, advanced hypertension, metabolic
syndrome, and insulin resistance are more
closely associated with ICAS

7. Stroke mechanisms in LAD
• Artery-to-artery embolism
• In situ atherothrombotic occlusion
• Hypoperfusion
• Branch occlusion

8. Artery-to-artery embolism
• unstable plaques - Plaque erosion or
ulceration, Intraplaque haemorrhage – plaque
rupture
• procoagulation environment, with abnormal
expression of tissue factor and plasminogen
activator inhibitor
• Local turbulence of blood flow and rupture of
a plaque into the bloodstream - promote
thrombus formation

9. • These thrombi are prone to be broken up by
forceful blood flow - migrate through the
bloodstream to occlude distant arteries,
resulting in clinical symptoms
• predominant stroke mechanism in patients
with ECAS and ICAS (i.e. proximal MCA to
distal MCA)

10. • less frequent in posterior circulation
• Significant atherothrombosis - proximal
vertebral artery
• Embolization to PCA, superior cerebellar
artery, posterior inferior cerebellar artery, and
the upper portion of the basilar artery

11. ay develop from the large
mal to the ICA, including the
tid artery, subclavian arteries,
ta and aortic arch
s develop more frequently in the
rch than in the ascending aorta,
e tends to occur in the left
e right

12. A 64-year-old hypertensive, diabetic man
developed dysarthria and left hemiparesis

13. In situ thrombotic occlusion
• ECAS - clinical consequences are not so grave
because of the ample collateral circulations in
the circle of Willis
• ICAS - produces significant cerebral infarction
as the collateral circulation is generally less
efficient
• well-developed collateral circulation, rarely
produces sudden, whole territory infarction

14. MCA steno-occlusion
• the initial lesions are usually restricted to the
striatocapsular and/or borderzone area
• As the occlusion continues, the initial infarct
frequently grows, accompanied by
progressive neurological worsening
• Ultimate infarct size varies according to the
status of the collateral circulation, the speed
of arterial occlusion and haemodynamic
stability after the occurrence of stroke

15. A 64-year-old hypertensive man developed mild
right hemiparesis and sensory aphasia.

16. The patient’s neurological symptoms
progressively worsened to have severe
right hemiparesis and global aphasia

17. Branch or perforator occlusion
• stroke mechanism unique to patients with
ICAS
• Atherosclerotic plaques in the intracranial
artery - occlude the orifice of the perforators
– infarcts limited to the subcortical area
• pathologic substrates - microdissection,
plaque haemorrhage, and platelet-fibrin
materials

18. • More often observed in posterior than in anterior
circulation stroke
• major mechanisms of brainstem stroke
• more easily recognized by imaging methodologies
such as MRA and CTA
• Mimic of lacunar stroke
• subcortical infarcts caused by branch occlusion tend
to extend to the basal surface whereas
• Lacune produces an island of ischaemic tissues
within the parenchyma

19. Subcortical infarction caused by branch
occlusion associated with focal intracranial
atherosclerosis

20. Left: obliteration of perforators by focal intracranial
atherosclerosis.
Right: junctional atherothrombosis

21. A 61-year-old hypertensive woman
presented with right hemipareisis
DWI showed a vertically extended infarct
in the left putamen/internal capsule
MRA – normal
High-resolution Vessel wall MRI - atherosclerotic
plaques in the superior wall of the left MCA trunk

22. Hypoperfusion
• continued atherosclerotic process - narrowing of the vessel -
turbulent blood flow and finally hypoperfusion distal to the
site of stenosis
• degree of hypoperfusion depends on the severity of vascular
stenosis/occlusion
• close correlation between the recurrence of ischaemic stroke
and the severity of occlusive disease
• occurrence of ischaemic events is also influenced by the
status of collateral flow from arteries at the circle of Willis,
external carotid artery system, and cervicothyroid arteries

23. • patients with severe vascular stenosis
/occlusion and insufficient collaterals -
haemodynamic TIAs
• Occur briefly and stereotypically in patients
who are dehydrated, fatigued, or at the time
when they suddenly stand up

24. • When stroke develops, the symptoms may
fluctuate widely according to the degree of
hydration, blood pressure, and the position of
the patient’s head
• Volume therapy or increasing patient’s blood
pressure is occasionally helpful in reversing
patients’ neurological deficits
• With persistent perfusion defect, the
symptoms may worsen gradually

25. • Although hypoperfusion is an important
stroke mechanism, strokes caused by
haemodynamic failure alone are uncommon
in clinical practice.
• More often, hypoperfusion plays an additive
role in the development of stroke, together
with other major stroke mechanisms

26. A 45-year-old man with hypertension, diabetes, and a history of
coronary heart disease developed
recurrent attacks of dizziness, diplopia, and gait instability that
lasted for a few minutes

27. Borderzone/ Watershed areas
• anterior circulation infarcts caused by
haemodynamic impairment
• superficial (ACA – MCA, MCA–PCA)
• internal (areas between superficial MCA pial
penetrators and lenticulostriate arteries)
• In the posterior circulation, haemodynamic
TIAs and strokes occur following severe steno-
occlusive lesions occurring in both vertebral
arteries or the basilar artery

28. A 50-year-old man with uncontrolled diabetes
mellitus developed mild left hemiparesis Gr 4

29. Two days later, the limb weakness
progressed to grade 2

30. MRA showed right internal
carotid artery occlusion

31. Small artery disease
• Causes a single subcortical infarction,
traditionally called a ‘lacunar infarction’
• pathological hallmarks - irregular cavities, less
than 15–20 mm in size
• located deep in the cerebral hemisphere,
brainstem, and the cerebellum

32. • Penetrating arteries associated with these lesions
are associated with disorganized vessel walls,
fibrinoid material deposition, and, occasionally,
haemorrhagic extravasation through arterial –
lipohyalinosis
• These vascular changes occur at arteries or arterioles
40–400 μm in diameter
• frequently affect the lenticulostriate branches of the
MCA, thalamoperforating arteries from the posterior
cerebral artery and the perforators of the basilar
arteries

33. Subcortical infarction presumably caused by
lipohyalinotic small artery disease

34. ‘atheromatous branch occlusion
(BAD)’
• lacunar infarctions - the atherosclerotic
process in the proximal part of the small
artery

35. Cardiac embolism
• Embolism from a diseased heart is the cause
of approximately 20–25% of ischaemic strokes
• most frequently travels to the MCA
• may affect any part of the brain, including the
subcortical and brainstem regions
• Infarcts are typically larger than those
associated with LAD, partly because the clots
are larger and partly because of the
insufficiently developed collateral circulation
in the absence of chronic atherosclerosis

36. • DWI detection of multiple acute infarcts in
multiple vascular territories suggests an
embolism from the heart rather than LAD
• Although the MCA trunk and/or branches are
the most frequently affected, larger vessels
such as the internal and common carotid
arteries may be occluded

37. • embolic materials are generally evanescent
• Recanalization of occluded vessels or
migration of emboli from proximal to distal
arteries
• Differentiate embolic from atherosclerotic in
situ occlusion
• Due in part to large lesion size and in part to
frequent recanalization (and reperfusion),
haemorrhagic transformation of an infarct is
relatively common

38. • Haemorrhagic transformation may be
associated with development of headache or
neurological worsening
• main concern in initiating anticoagulation
therapy

39. A 71-year-old woman with atrial fibrillation
suddenly developed confusion

40. Follow up scan 4 days later

41. ‘GRE susceptibility
vessel sign’ (GRE SVS)
• characteristics of an intraluminal clot differ
according to the origin of the thrombus
• White thrombi formed in areas of high shear
stress are composed predominantly of
platelet aggregates
• red thrombi formed in low-pressure areas
such as cardiac chambers are rich in fibrin and
trapped red blood cells
• thrombus showing a GRE SVS sign contains a
large quantity of red blood cells

42. A 61-year-old woman with atrial fibrillation presented
with right hemiparesis and aphasia

43. Cardiac diseases producing
embolic infarction

44. Atrial fibrillation
• most common cause of embolic infarction
the following characteristics are shown to
increase the risk of stroke
• previous embolic events, advanced age
• hypertension, diabetes
• associated cardiac problems such as
rheumatic valve disease, left ventricular
dysfunction, and enlarged atrium

45. CHADS 2 and CHA2DS2 -VASc score

46. Patent foramen ovale
• combination of patent foramen ovale (PFO)
and right-to-left shunting is a potential source
of embolism
• Studies have confirmed that thrombi arising in
the venous system travel to occlude cerebral
arteries through a right-to-left cardiac shunt
(paradoxical embolism)
• suspected embolism but without a clear
source - transoesophageal echocardiography
with shunt tests

47. Uncommon causes or mechanisms
of stroke
• dissection, moyamoya disease,arteritis,
coagulation abnormality, and CADASIL

48. Cryptogenic (undetermined)
stroke
• when there is an incomplete workup, two or
more possible mechanisms, or when the
cause is undetermined despite adequate
workup
• less than 20%

49. CLASSIFI CATION OF STROKE BASED
ON STROKE MECHANISMS

50. TOAST
• With improved understanding of the
pathophysiology of ischaemic stroke - need to
classify stroke
• The first, and still most widely used
classification system using such criteria was
• Trail of ORG 10172 in acute stroke treatment

51. STROKE SUBTYPES
Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter
clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.
Adams HP Jr, Bendixen BH, Kappelle LJ, Biller J, Love BB, Gordon DL, Marsh EE 3rd
Stroke. 1993;24(1):35.

52. • One of the limitations of the TOAST system is
the high (approximately 40%) proportion of
‘SUC’
• another system that modified the original
TOAST was introduced(SSS-TOAST, Stop
Stroke Study Trial of Org 10172) - to identify
the most probable TOAST category in the
presence of evidence for multiple
mechanisms, thereby decreased the
proportion of patients with SUC

53. • each TOAST subtype was subdivided into
three subcategories as ‘evident’, ‘probable’,
or ‘possible’ according to predefined specific
clinical and imaging criteria
• An automated version of the SSS-TOAST, the
Causative Classification System (CCS) - web-
based system that consists of questionnaire-
style classification scheme for ischaemic
stroke (< http://ccs.martinos.org > ), and
allows rapid analysis of patient data

54. • Another system - ‘A–S–C–O’ - phenotype-
based classification
• every patient is characterized by A–S–C–O: A
for atherosclerosis, S for small vessel disease,
C for cardiac source, O for other cause

55. References
• Bradley’s Neurology in Clinical Practice 7th
• Oxford Textbook of Stroke and
Cerebrovascular Disease
• Arsava EM , Ballabio E , Benner T , Cole JW ,
Delgado-Martinez MP ,Dichgans M , et al . The
Causative Classification of Stroke system:
aninternational reliability and optimization
study. Neurology.

56. • Amarenco P , Bogousslavsky J , Caplan LR ,
Donnan GA , Hennerici MG. New approach to
stroke subtyping: the A-S-C-O (phenotypic )
classifi cation of stroke. Cerebrovasc Dis. 2009

57. THANKS