Pathophysiology of ISchemic Stroke

Pathophysiology of ISchemic Stroke

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. embolisms may develop from the large arteries proximal to the ICA, including the common carotid artery, subclavian arteries, ascending aorta and aortic arch Aortic plaques develop more frequently in the distal aortic arch than in the ascending aorta, embolic stroke tends to occur in the left rather than the 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 T rail of O RG 10172 in a cute stroke t reatment

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 7 th 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: an international 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