1) Stroke is defined as acute neurological dysfunction caused by abnormal blood supply to the brain. The two main types are ischemia and hemorrhage. 2) Ischemia is caused by thrombosis, embolism, or decreased blood flow. Hemorrhage includes intracerebral, subarachnoid, subdural, and epidural bleeding. 3) At the cellular level, ischemia triggers an excitotoxic cascade involving glutamate, sodium/calcium influx, oxidative stress, and apoptosis, ultimately leading to cell death. Maintaining cerebral blood flow is crucial for preventing neurological injury.

1. ETIOPATHOGENESIS OF
SROKE
Dr Srija Inuri
PG Registrar

2. Definition
• Stroke refers to any damage to the brain or the spinal cord caused by
an abnormality of the blood supply.(Caplan-texbook of stroke)
• Stroke is defined as an "acute neurological dysfunction of vascular
origin with sudden(within seconds) or atleast rapid(with in hours)
occurrence of symptoms and signs corresponding to involvement of
focal areas in the brain"(Goldstein, Barnet et al, 1989)

3. Epidemiology
• Stroke (including ischaemic stroke and haemorrhagic stroke) affects
13.7 million people globally per year and is the second leading cause
of death, with 5.5 million deaths per year
• An estimated 1 in 4 adults will experience a stroke in their lifetime
• The estimate includes an almost equal risk of stroke among women
and men in Global Burden of Disease Study 2016.

4. PATHOLOGY OF STROKE
• two major categories
• (1) ischemia, which is a lack of blood flow depriving brain tissue of
needed fuel and oxygen;
• thrombosis, embolism, and decreased systemic perfusion
• (2) hemorrhage, which is the release of blood into the brain and into
extravascular spaces within the cranium.

5. Ischemic stroke
• Thrombotic stroke (large vessel and small vessel types)
• Embolic stroke (with/without known cardiac and/or arterial
factor)
• Systemic hypoperfusion (Watershed or Border Zone stroke)

6. Hemorrhagic stroke
• Intracerebral
• Subarachnoid
• Subdural
• Epidural

7. Thrombosis-Large vessel disease
• Atherosclerosis affects chiefly large arteries
Less common causes include
• primary hematologic problem
• fibromuscular dysplasia
• arteritis,
• dissection of the vessel.

8. Small Vessel Disease
• Thrombotic occlusion of the small penetrating arteries
• 20% to 30% of all ischemic strokes.
• Strongly associated with hypertension
• Characterized pathologically by
– lipohyalinosis,
– microatheroma,
– fibrinoid necrosis,

9. Embolism
• In embolism, material formed elsewhere within the vascular system
lodges in an artery and blocks blood flow.
Two main sources
• Cardiac
• Artery-artery
• Paradoxical emboli

10. Decreased Systemic Perfusion
• Diminished flow to brain tissue
• cardiac pump failure (most often due to myocardial infarction or
arrhythmia)
• systemic hypotension (due to blood loss or hypovolemia).
• Responsible for watershed infarcts.

13. Subarachnoid Hemorrhage
• originates from
1. aneurysms
2. arteriovenous malformations,
3. bleeding diatheses or
4. Trauma
• Ischemia is because of
• increasing intracranial pressure
• Vasoconstriction-blood within the subarachnoid space often contains
substances that promote vasoconstriction of the basal arteries that are
bathed in cerebrospinal fl uid.

14. Intracerebral Hemorrhage/Parenchymal Hge
• bleeding directly into the brain substance.
1. Hypertension
2. Bleeding diatheses, especially from Iatrogenic prescription of
anticoagulants or
3. Trauma,
4. vascular malformations,and vasculopathies(such as cerebral
amyloid angiopathy),
• Intracerebral hemorrhages are at first soft and dissect along white
matter fiber tracts.When bleeding dissects into the ventricles or onto
the surface of the brain, blood is introduced into the cerebrospinal
fluid may hamper CSF absorption leading to communicating
hydrocephalus.

15. Subdural and Epidural Hemorrhages
• almost always caused by head trauma.
• Subdural hemorrhages arise from injured veins. Bleeding is most
often slow and accumulates during days, weeks, and even a few
months.
• Epidural hemorrhages are caused by tearing of meningeal arteries,
most often the middle meningeal artery. Blood accumulates rapidly
over minutes to hours
• Both cause symptoms and signs by compressing brain tissue and
increasing intracranial pressure

16. Normal Metabolism and Blood Flow
• Brain uses about one quarter of the body’s energy supply.
• Brain cells depend mainly on oxygen and glucose (sole substrate for
energy metabolism) to survive.
• Glucose is oxidized to carbondioxide (CO2) and water (H2O)-ATP
• To keep the major extracellular cations Ca (calcium ions) and Na
(sodium ions) outside the cells and the intracellular cation K
(potassium ions) within the cells.
• uses approximately 500 mL of oxygen and 75 to 100 mg of glucose
each minute, a total of 125 g of glucose each day

17. Cerebral Blood Flow
• Brain constituttes for 2% of adult body weight,uses 20% of
cardiac output in resting state.
• Normal cerebral blood flow (CBF) is approximately 50-to 60
ml/100g/ Min.
• In response to ischemia, the cerebral autoregulatory
mechanisms compensate for a reduction in CBF.

18. Autoregulation
• The capacity of the cerebral circulation to maintain relatively constant
levels of CBF despite changing blood pressure .
(80–150mmHg)
• The range of autoregulation is shifted to the right, i.e. to higher values,
in patients with hypertension and to the left during hypercarbia.

20. Autoregulatory mechanisms
• The myogenic theory of autoregulation: changes in vessel diameter
caused by the direct effect of blood pressure variations on the myogenic
tone of vessel walls.
1. By local vasodilatation
2. Opening the collaterals
3. Increasing the extraction of oxygen and glucose from the blood

21. • Development of permanent neurologic sequelae is a time
dependent process; for any given blood flow level, low
CBF values are tolerated only for a short period

22. • Schematic drawing of the different cerebral
blood flow thresholds in man.
Between CBF values of 22 mL/100 mg/min to 8
mL/100 mg/min, brain tissue maintains its
structural integrity and, most importantly, can be
salvaged with reperfusion.

25. Ischemic stroke

26. Ischemic core/penumbra
• Ischemic core - irreversibly damaged tissue
• The ischemic penumbra represents tissue that is functionally
impaired but structurally intact and, as such, potentially
salvageable.
Salvaging this tissue by restoring its flow to nonischemic levels is
the aim of acute stroke therapy.

27. • Area of oligemia - represents mildly hypoperfused tissue from the
normal range down to around 22 mL/100 mg/min.
• Usually not at risk of infarction
• In hypotension, fever, or acidosis, oligemic tissue can be
incorporated into penumbra and subsequently undergo infarction.

28. IMPAIRED PERFUSION >3 MINUTES –
DECREASE IN ATP
MITOCHONDRIA – LOSS OF INCOMING
OXYGEN
ANAEROBIC GLYCOLYSIS
RELEASE OF OXYGEN FREE
RADICALS
ACCUMULATION OF
LACTIC ACID
INFLAMMATION
DAMAGE TO
BLOOD BRAIN
BARRIER
EDEMA

29. Thrombus formation
• three types of thrombi
• Red thrombi are composed mostly of red blood cells and fi brin, and
they form in areas of slowed blood flow.
• White thrombi, in contrast, are composed of platelets and
fibrin exclusively in areas in which the arterial wall or endothelial
surface is abnormal
• Disseminated fi brin deposition in smallvessels

31. Effects at cellular level

32. Ischemic cascade
Excitotoxicity
Oxidative
stress
Apoptosis

33. Excitotoxicity
• Excitotoxicity is the pathological process by which neurons are
damaged by the overstimulation of receptors by the excitatory
neurotransmitter glutamate, such as the NMDA receptor and
AMPA receptor.
Doble A. The Role of Excitotoxicity in Neurodegenerative Disease: Implications for Therapy. Pharmacol Ther. 1999; 81(3): 163-221.

34. Excitotoxicity
• Excitotoxicity is the pathological process by which neurons are
damaged and killed by the overreactions of receptors for the
excitatory neurotransmitter glutamate, such as the NMDA
receptor and AMPA receptor.
Doble A. The Role of Excitotoxicity in Neurodegenerative Disease: Implications for Therapy. Pharmacol Ther. 1999; 81(3): 163-221.

35. Classic pathway
Events
leading to
sodium
influx
Events
leading to
calcium
influx
Exocytosis
of
glutamic
acid

36. • In the ischemic zone, the glutamate binds to postsynaptic
receptors which triggers increased calcium influx through
glutamate receptor-coupled ion channels.

37. • Glutamate overstimulates
-N-methyl-D-aspartate (NMDA)
-alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid
(AMPA) and
-kainite-type glutamate receptors
• Results in sodium influx and potassium efflux through the
glutamate receptor activated membrane channels.

38. • NMDA channels are highly permeable to calcium and
contribute to the influx of calcium into the cell.
• The influx of calcium from the extracellular fluid is thought to
be the primary factor in calcium contributory mechanisms of
cell death after ischemic stroke

39. Lo E, Dalkara T, Moskowitz M. Mechanisms, challenges and opportunities in
stroke. Nature Reviews. 2003; 4: 399-415

40. Increased calcium levels in the cytosol
Increased activation of calcium-dependent synthases and proteases
• Degradation of cytoskeletal and enzymatic proteins
• Increased levels of nitric oxide and peroxynitrite within the cell through
activation of degrading enzymes such as phospholipase, proteases and
endonucleases.

41. • The potassium efflux through the NMDA channels and other ion imbalances can
increase caspase activity, triggering apoptosis.
• The primary caspases responsible for apoptosis due to ischemic stroke are
caspases 9 and 3.
• Caspase 9 activates caspase 3.
• Caspase 3 degrade substrate proteins within the cell and produce
internucleosomal endonuclease activity and DNA fragmentation.

42. Oxidative stress
• A potential pathway for cellular damage in ischemic stroke may be
the occurence of oxidative stress, which is the increased
occurrence of reactive oxygen species (ROS) above physiological
levels.
• Free radicals can cause membrane damage through peroxidation of
unsaturated fatty acids in the phospholipids making up the cell
membrane

43. Image retrieved
from http://journals.prous.com/journals/dot/20033901/html/dt390019/images/
Kulkarni_f4.gif

44. Apoptosis
• Apoptosis is a form of programmed cell death, which involves :
Shrinkage of the cell cytoplasm
Cleavage of DNA within the nucleus
Condensation of chromatin in the nucleus
Formation of apoptotic bodies,
Cell death

45. Mechanisms
Intrinsic
mechanisms
Mitochondria
mediated
Endoplasmic
reticulum
mediated
Extrinsic
mechanisms
Death
receptors
Caspases

46. Mitochondria mediated
• Translocation of pro-apoptotic Bcl-2 members like Bax into the
mitochondria, a cascade of events are triggered .
• This leads to mitochondria releasing substances such as
cytochrome c, procaspase-9, and Apaf-1 from its
intermembrane space .
Lotocki G and Keane R. Inhibitors of Apoptosis Proteins in Injury and Disease.
Life. 2002; 54: 231-240

47. Endoplasmic reticulum
• The ER initiates unfolded protein response (UPR) .
• During this UPR, three ER transmembrane effector proteins are
activated (PERK, IRE1, and ATF-6).
• IRE1 has been shown to be involved in the activation of
caspase-12 .
Nakka VP, Gusain A, Mehta SH, Raghubir R. Molecular mechanisms of apoptosis in cerebral ischemia: multiple neuroprotective opportunities. Mol
Neurobiol. 2008; 37:7-38

48. Extrinsic mechanisms
• Death receptors are tumor necrosis factor receptors (TNFR)
and include TNFR-1, Fas, and p75 .
• A transcription factor, Forkhead1, stimulates the expression of
genes including Fas ligand (FasL).
• FasL initiates apoptosis by binding to the Fas receptor and
recruiting the Fas-associated death domain protein (FADD)

49. Factors Affecting Tissue Survival
(1) the adequacy of collateral circulation,
(2) the state of the systemic circulation,
(3) serologic factors,
(4) changes within the obstructing vascular lesion, and
(5) resistance within the microcirculatory bed

51. Conclusions
• The local and systemic effects that occur after a stroke, such as the
immune response and excitotoxicity, have lasting effects on the
amount of function and independence a person can regain after a
stroke.
• It is paramount to understand the cell biology mechanics that occur
prior to and following a stroke in order to mount the most effective
response and diminish the subsequent injury to the brain and body
following the initial insult.

52. • THANK YOU

53. References
• Text book of stroke-Caplan
• Ischemic stroke: Pathopysiology and principles of localisation,
Neurology board review manual: Mathew Brandon Mass,
Joseph E Safdieh.
• Pathophysiology, treatment, and animal and cellular models of
human ischemicstroke Woodruff TM, Thundyil J, Tang SC, Sobey
CG, Taylor SM, Arumugam TV.Mol Neurodegener. 2011 Jan
25;6(1):11. doi: 10.1186/1750-1326-6-11.