pathophysiology of cerebral ischemia and infarction

1. Cerebral ischemia and infarction
Dr . N. Vinay Kumar
DM Neurology resident

2. CEREBRAL ISCHEMIA
• It is potentially reversible altered state of brain physiology and biochemistry that
occurs when substrate delivery is cut off or substantially reduced by vascular
stenosis or occlusion.
• Stroke is defined as an acute neurologic dysfunction of vascular origin with
sudden (within sec) or atleast rapid occurrence of symptoms and signs
corresponding to involvement of focal areas in the brain.

3. Pathological alterations in cerebral vessel function
1. Platelets and PMN release vasoactive amines include ADP,TXA2 and
serotonin reduce or inhibit NO Vasoconstriction.
2. Atherosclerosis excess production of ROS decrease NO
bioavailabilty impaired endothelial dep relaxation.
3. Statins are pleotropic improve vascular function by increase in NOS
and reduced NADPH oxidase and Rho kinase.
4. Chronic hypertension oxidative stress and elevated ROS
inactivation of NO and endothelial dysfunction

5. 6.Impaired function of many K+ channels leads in cerebral artery
dysfunction and vasoconstriction

6. 6.SAH leads to cerebrovascular depolarisation and results in vasospasm
due to impaired endothelial dep relaxation,reduced guanyl cyclase,
bilirubin oxidation products and reduced K+ channel function

7. 7)Diabetes – hyperglycemia leads to impaired endothelial vascular
dilatation due to activation of EDCF protein C kinase.
8. Hyperhomocystenemia leads to endothelial dysfunction due to
increased levels of S adenosine methionine levels.

8. Cerebral stroke subtypes
ischemic
thrombotic
embolic
hemorrhagic
intracerebral
subarachnoid

9. Risk factors

10. Thrombosis
• Refers to an obstruction of blood flow due to a localised occlusive process within
one or more blood vessels.
• The lumen of the vessel is narrowed or occluded by an alteration in the vessel
wall or by superimposed clot formation.
• The most common type of vascular pathology is atherosclerosis.

12. Atherosclerosis
• Fibrous and muscular tissues overgrow in the sub intima.
• Fatty materials form plaques that can encroach on the lumen.
• Platelets adhere to plaque and form clumps that serve as nidus for the deposition
of fibrin, thrombin, and clot.
• Affects chiefly the larger extracranial and intracranial arteries.
• The smaller, penetrating arteries are more often damaged by hypertension than
by atherosclerotic processes.

14. • Less common vascular pathologies leading to obstruction include
Fibromuscular dysplasia
Arteritis
Dissection of the vessel wall
Hemorrhage into plaque
• At times, the focal vascular abnormality is a functional change in the
contractility of blood vessel
• Intense focal vasoconstriction can lead to decreased blood flow and
thrombosis.

15. Embolism
• Material formed else where within the vascular system lodges in an artery and blocks
blood flow.
• Blockage can be transient or may persist for hours or days.
• Most commonly :heart
• Other sources: 1)major arteries such as aorta, carotid and vertebral arteries.
2)systemic veins.

16. Decreased systemic perfusion
• Diminished flow to brain tissue is caused by low systemic perfusion pressure.
• Most common causes are:
1)Cardiac pump failure: due to Myocardial infarction.
2)Systemic hypotension: due to blood loss or hypovolemia.
• Lack of perfusion is more generalised than in localised.
• Poor perfusion is most critical in border zone or called as watershed regions.

17. Damage caused by ischemia
• All 3 mechanisms lead to temporary or permanent tissue injury.
• Permanent injury is termed as infarction.
• Capillaries or other vessels within the ischemic tissue may also be injured.
• Reperfusion can lead to leakage of blood into the ischemic tissue resulting in
hemorrhagic infarction.
• Extent of brain damage depends on
1) Location and duration of the poor perfusion.
2) Ability of collateral vessels to reperfuse the tissues at risk.

18. • The systemic blood pressure, blood volume, and blood viscosity also affect blood
flow to the ischemic areas.
• In acute phase:
Brain and vascular injuries may lead to brain edema during the hours and days after
stroke.
• In chronic phase:
Macrophages gradually ingest the necrotic tissue debris within the infarct leading
to shrinkage of infarct and forms gliotic scars.

19. Cerebral microvessel response to focal ischemia
1. Loss of barrier leading to endothelial cell
permeability with subsequent edema
2. Loss of basal lamina and extracellular matrix with
haemorrhagic transformation
3. Alteration in cell matrix adhesion
4. Loss of microvessel patency
5. Generation endothelial and leucocyte adhesion
molecules

20. • Capilllary permeabilty barrier function is lost in 30 min after ischemia
swelling of endothelial and astrocytes with cytoplasm reorganization
Capillary expands and rupture
Accumulation of fluid in extravascular space
Swelling leads to focal no flow phenomena
• Bradykinin,vegf,MMP,thrombin and protease leads to loss of BBBand microvas ECM
• Decrease in laminin and fibronectin leads to leakage of blood
• Beta integrin, p selectin and E selectin are involved in ECM disturbed due to cytokines by glial
cells

21. • Proteolysis of microvascular matrix
Loss of basal lamina
Increase in pro MMP 2, urokinase and plasminogen activator inhibitor
Leads to matix and parenchymal degeneration
• Microvessel cell adhesion- after injury beta integrins and dystroglycan on endothelial cell reduces the adhesion.
• Focal no flow phenomenon and secondary injury-transient occlusion of brain supplying artery significantly reduces patency of
distal microvascular bed .
• Could be external or internal compression

22. • Initiation of cellular inflammation
Ischemia secondary injury to vessels inflammation obstruction
by WBC and platelet adhesion
•
Leucocyte diapedesis. Leucocytes interact with endothelial cells expressing P selectins through P-selectin
glycoprotein 1 (PSGL-1), leading to their“rolling” on the endothelial surface. Interaction of leucocyte integrins
CD11a/CD18 and CD11b/CD18 with intercellular adhesion molecule 1 (ICAM-1) leads to firm adherence and
aggregation of leucocytes. Diapedesis of leucocytes is facilitated by platelet-endothelial cell adhesion molecule
1 (PECAM-1).

23. • Fibrin formation and deposition
Fibrinogen exposed to tissue factor leads to formation of fibrin
Activated platelets +fibrin
Vascular obstruction in capillaries and venules
• Hemostasis
Occurs by expression of activators and inhibitors of thrombosis in
vessel walls or by cross talk between vascular cell components
TF is the activator of coagulation and breach in endothelium leads to
contact of TF and coagulation.

25. Physiology and pathophysiology of brain
ischemia
Normal Metabolism and Blood Flow:
• Brain uses glucose as its sole substrate for energy metabolism.
• Glucose metabolism leads to conversion of ADP to ATP.
• A constant supply of ATP is needed to maintain neuronal integrity and to keep the
major extracellular Ca++ and Na+ outside the cells and the intracellular K+ within
the cells.
• Production of ATP is much more efficient in the presence of oxygen.

26. • In absence of oxygen anaerobic glycolysis leads to formation of ATP and lactate,
the energy yield is relatively small, and lactic acid accumulates within and outside
the cells.
• Brain requires 75 to 100 mg of glucose each minute.
• Normal CBF =50-55ml/100g/minute.
• Cerebral oxygen consumption, is normally 3.5ml/100g/minute.
• By increasing oxygen extraction from the blood stream, compensation can be
made to maintain until CBF is reduced to a level of 20 to 25ml/100g/minute.

27. • Brain energy use and blood flow depend on the degree of neuronal
activity.
• In response to ischemia , the cerebral autoregulatory mechanisms
compensate for a reduction in CBF.

28. 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 left during hypercarbia.

29. Maintenance of cerebral blood flow by autoregulation typically occurs within a mean arterial pressure range of 60-150mmHg

30. 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 the vessel
walls.
1) By local vasodilatation
2) Opening the collaterals.
3) Increasing the extraction of oxygen and glucose from the blood.

31. Cerebral autoregulation during stroke

32. Between CBF Values of 22ml/100mg/min to 8mL/100mg/min,brain tissue maintains its structural integrity
and can be salvaged with reperfusion.

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

35. • Core of the infarct:
• Center of the zone where the blood flow is lowest
• Neurons undergoes necrosis.
• CBF ranges from 0 to 10ml/100g/min.
• Ischemic penumbra:
• Zone of reduced perfusion in the periphery.
• CBF ranges from 10 to 20ml/100g/min.
• Electrical failure but not permanent damage.
• Restoration of blood results in survival.
• If blood flow is not restored cells undergo death by apoptosis.

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

37. impaired perfusion >3min
decrease in ATP
↓
mitochondria –loss of incoming oxygen
↓
anaerobic glycolysis
release of free radicals accumulation of lactic acid
inflammation Damage Edema
to BBB

38. Local Brain Effects of Ischemia
• Survival of the at-risk tissue depends on
1. Intensity and duration of the ischemia.
2. The availability of collateral blood flow.
CBF:
-approx.=20ml/100g/min-EEG activity is affected.
-<20ml/100g/min-cerebral O2 consumption falls.
-<10ml/100g/min-membranes and functions are affected
-<5ml/100g/min-neurons cannot survive for long.
• When neurons become ischemic, a number of biochemical changes potentiate
and enhance cell death.

40. These biochemical effects are:
• K+ moves out the cell and Ca2+ moves into the cell leads to failure of membrane
function and mitochondrial failure.
• Decreased oxygen availability leads to formation of oxygen free radicals.
• These free radicals cause peroxidation of fatty acids in cell organelles and plasma
membranes, causing severe cell dysfunction.
• Anerobic glycolysis leads to an accumulation of lactic acid and decrease in pH.
• The resulting acidosis also greatly impairs cell metabolic functions.

41. • Excitatory neurotransmitters(glutamate, aspartate ) is significantly increased in
regions of brain ischemia.
• Hypoxia , hypoglycemia and ischemia all contribute to cause energy depletion
and an increase in glutamate release but a decrease in glutamate uptake.
• Glutamate entry opens membranes and increases Na+ and Ca2+ influx into cells.
• Large influxes of Na are followed by entry of chloride ions and water, causing cell
swelling and oedema.
• Glutamate is an agonist at both NMDA and non NMDA receptors types, but only
NMDA receptors are linked to membrane channel with high calcium permeability.

42. • All these metabolic changes cause a self perpetuating cycle leading to more local
biochemical changes, which in turn cause more neuronal damage.
• At some point, the process of ischemia becomes irreversible, despite of
reperfusion.
• At times, although the severity of ischemia is insufficient to cause neuronal
necrosis, ischemia may cause programmed cell death referred to as apoptosis.

43. Effects at cellular level

44. Excitotoxicity
• 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.

45. Fig. 1. The dual role of NMDA receptors in determining the fate of neurons: binding of glutamate to
extrasynaptic NMDARs dephosphorylates cAMPresponsive element-binding protein (CREB), inactivates
the extracellular signal-regulated kinase (ERK) pathway and promotes cell death, while binding of
glutamate to synaptic NMDARs promotes cell survival through activation of the phosphoinositide-3-kinase
(PI3K)/Akt pathway, which inactivates glycogen
synthase kinase 3β (GSK3β), the pro-apoptotic Bcl-2 associated death promotor (BAD), pro-apoptotic p53,
and c-Jun N-terminal kinase (JNK)/p38 activator apoptosis signal-regulating kinase 1 (ASK1)

46. • In the ischemic zone, the glutamate binds to postsynaptic receptors which
triggers increased calcium influx through glutamate receptor-coupled ion
channels.
• Glutamate overstimulates NMDA, AMPA, Kainite type glutamate receptors.
• Results in sodium influx and potassium efflux through the glutamate receptor
activated membrane channels.
• NMDA channels are highly permeable to calcium and contribute to influx of
calcium from extracellular space and results in cell death after ischemic stroke.

47. increased calcium levels in cytosol
↓
Increased activation of calcium dependent synthases and proteases
↓
Degradation of cytoskeletal and enzymatic proteins
Increased levels of NO and peroxynitrite within the cell through
activation of degrading enzymes such as phospholipase, proteases and
endonucleases.

48. • Potassium efflux through NMDA channels can increase caspase
activity, triggering apoptosis.
• 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.

50. Oxidative stress
• A potential pathway for cellular damage in ischemic stroke may be
the occurrence of oxidative stress, which is the increased occurrence
of ROS above physiological levels.
• Free radicals can cause membrane damage through peroxidation of
unsaturated fattyacids in the phospholipids making up the cell
membrane.

54. Apoptosis
• 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

56. 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 from its intermembrane space.

57. Main pathways are leading to apoptosis. Opening of the mitochondrial permeability transition pore (MPTP) leads to the release of cytochrome C
(cyt C), which together with the cytosolic apoptotic-protease-activating factor-1 (Apaf-1) activates procaspase-9. Active caspase-9 further activates
caspases-3 and 7, leading to the execution phase of caspase-dependent apoptosis. The mitochondria also release apoptosis-inducing factor (AIF),
high-temperaturerequirement protein A (HtrA2/OMI), as well as a second mitochondrion-derived activator of caspase/direct inhibitor of apoptosis-binding
protein with low pI (SMAC/DIABLO), which inhibits the antiapoptotic X chromosome-linked inhibitor-of-apoptosis protein (XIAP), thereby leading to
apoptosis The binding of Fas ligands (FasL) to Fas receptors recruits the cytoplasmic Fas-associated death domain (FADD) and pro-caspase-8, forming
together the death-inducing signaling complex (DISC), which leads to activation of pro-caspase-8 and triggering of the extrinsic pathway of apoptosis.

58. Endoplasmic reticulum
• ER initiates unfolded protein response(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.

59. Cerebral edema and increased intracranial
pressure
• There are 2 types of cerebral edema:
1)Cytotoxic edema
2)Vasogenic edema
leads to shifts in position of brain tissue and herniation of brain contents from one
compartment to another.

60. Cytotoxic edema:
• Water accumulation inside cells.
• Caused by energy failure, with movement of ions and water across the cell
membranes into cells.
• Brain swelling caused by cytotoxic edema means a large volume of dead or dying
brain cells, which implies bad outcome.
• Usually seen after arterial occlusion due to energy failure.

61. Vasogenic edema
• Fluid within the extracellular space.
• Influenced by hydrostatic pressure factors and by osmotic factors.
• Breakdown of BBB→proteins and other macromolecules enter the Extracellular
space→exert osmotic gradient→pulling water into the extracellular space.
• Preferentially involves cerebral white matter.

63. Ischemic cascade
Lack of oxygen supply to ischemic neurones
ATP depletion
Membrane ions system stops functioning
Depolarisation of neuron
Influx of calcium
Release of neurotransmitters, including glutamate, activation
of N-metyl -D- aspartate and other excitatory receptors
at the membrane of neurones
Further depolarisation of cells
Further calcium influx

67. Thank you

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