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PATHOPHYSIOLOGY OF CEREBRAL ISCHEMIA Prof. J. HANACEK, M.D., Ph.D.

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Presentation on theme: "PATHOPHYSIOLOGY OF CEREBRAL ISCHEMIA Prof. J. HANACEK, M.D., Ph.D."— Presentation transcript:

1 PATHOPHYSIOLOGY OF CEREBRAL ISCHEMIA Prof. J. HANACEK, M.D., Ph.D.

2 Anatomy of brain vessels

3 Carotic and vertebral arteries

4 View to medulla, brainstem and inferior brain vessels

5 Brain arteries - anterior and posterior circulation

6 Brain arteries – lateral view

7 Brain arteries: lateral and medial aspects

8 Cerebral vascular events - sudden damage of brain induced by decreasing or suspending substrate delivery (oxygen and glucose) to the brain due to disturbaces of brain vessels Classification of cerebral vascular events (cerebral strokes) 1. focal cerebral ischemia (the most often–80-88%) 2. intracerebral hemorrhage (9-15%) 3. subarachnoid hemorrhage (3-5%) Normal values of cerebral blood flow Cerebral blood flow (Q): cortex ml/g/min white matter – 0.2ml/g/min white matter – 0.2ml/g/min

9 Types of Stroke

10 Epidural hematoma

11 Subfrontal and occipital hematoma

12 Distribution of congenital cerebral aneurysms

13 Arteria cerebri media and penetrating arteries

14 Microaneurysms in penetrating arteries

15 Intracerebral hemrrhage

16 Definitions of cerebral ischemia It is the 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 seconds) or at least rapid (within hours) occurence of symptoms and signs corresponding to the involvement of focal areas in the brain“ (Goldstein, Barnet et al, 1989)

17 A. Etiopathogenesis of cerebral ischemia Main pathogenetic mechanisms: 1. microembolisation to brain vessels ( due to myocardial infarction, mitral valve damage, others) myocardial infarction, mitral valve damage, others) 2. stenosis of cerebral artery + decreasing of systemic blood pressure systemic blood pressure 3. tromboembolism of large brain vessels 4. decreased cardiac output (due to decreased myocardial contractility, massive hemorrhage, others) myocardial contractility, massive hemorrhage, others)

18 Cardiac sources of cerebral emboli

19 B. Pathogenetic mechanisms involved in development of cerebral ischemia (CI) development of cerebral ischemia (CI) 1. The brain is protected against focal interruption of 1. The brain is protected against focal interruption of blood supply by a number of extra- and intracranial blood supply by a number of extra- and intracranial collateral vessels collateral vessels a) number and vascular tone of the leptomeningeal collateral channels collateral channels b) blood viscosity c) blood perfusion pressure Actual size of the cerebral ischemia depends on:

20  The rich anastomotic connections between the carotid and vertebral arteries provide a powerfull collateral and vertebral arteries provide a powerfull collateral system which is able to compensate for the occlusion system which is able to compensate for the occlusion of up to three of these arteries (known from animal of up to three of these arteries (known from animal experiment) experiment)  The good collateral system results in lesser ischemic area than is a territory supplied by occluded artery area than is a territory supplied by occluded artery  The bad collateral system results in ischemic area equal to a territory supplied by ocluded artery to a territory supplied by ocluded artery

21  since these regions represent the border lines between the supplying territories of the main cerebral arteries, the the supplying territories of the main cerebral arteries, the resulting lesion have been termed "border zone" or resulting lesion have been termed "border zone" or watershed infarcts watershed infarcts   systemic BP + multifocal narrowing of extracerebral arteries  blood flow initially in the periphery of arteries  blood flow initially in the periphery of arterial territories arterial territories Mechanisms ivolved in failure of collateral system   systemic BP   blood flow through collateral circulation  base for hemodynamic circulation  base for hemodynamic theory of stroke development theory of stroke development

22 Types of ischemic and hemorrhagic stroke

23 Ischemic cascade Lack of oxygen supply to ischemic neurones ATP depletion Membrane ions system stops functioning Depolarisation of neurone 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 Carrol and Chataway,2006

24 Energy failure / depolarisation Transmitter release and receptor activation Ca 2+ Ca 2+ Lipolysis (DAG  PKC  )  Protein Proteinphosphorylation ProteolysisDisaggregation of microtubuli (FFAs .LPLs  ) Enzymeconversion Breakdown of cytoskeleton Damage to membrane structure and function Dysfunction of receptors and ion channels Free radical formation Inhibition of axonal transport, blebbing Cosequences of brain ischemia

25 Úplná ischémia Hypoglycemia SD Penumbra Total ischemia Ischemia Intra- and extracellular changes of Ca ++ exc inc

26 Spreading depression (SD) waves - occur in focal cerebral ischemia of the brain - a selfpropagating neurohumoral reaction mediated by release of potassium ions and excitotoxic amino acids from depolarized areas of cerebral cortex - depolarization of neurons and astrocytes and up-regulation of glucose consumption, is thought to lower the threshold of neuronal death during and immediately after ischemia (Miettinen et al., 1997) - COX-2, the inducible form of the enzyme converting arachidonic acid to prostaglandins, is induced within hours after SD and transient focal ischemia in perifocal cortical neurons by a mechanism dependent on NMDA-receptors and PLA2 (Miettinen et al., 1997) - preconditioning CSD applied 3 days before middle cerebral artery occlusion may increase the brain's resistance to focal ischemic damage and may be used as a model to explore the neuroprotective molecular responses of neuronal and glial cells (Matsushima et al., 1996)

27 2. Hemorheology and microcirculation - their importance in development CI Relationship between blood viscosity and microcirculation : and microcirculation : Q = flow rate  P = pressure gradient r = radius of tube l = length of the tube  = viscosity of the fluid  P. r 4  P. r 4 Q = . 8. l . 8. l

28 It is clear that flow rate (Q) indirectly depends on blood It is clear that flow rate (Q) indirectly depends on blood viscosity – Q will decrease with increase blood viscosity viscosity – Q will decrease with increase blood viscosity Blood viscosity depends on: Blood viscosity depends on: - hematocrit, - hematocrit, - erythrocyte deformibility, - erythrocyte deformibility, - flow velocity, - flow velocity, - diameter of the blood vessels - diameter of the blood vessels In the brain macrocirculation (in vessels larger than 100  ): Blood viscosity depends mainly on: - hematocrit, - hematocrit, - flow velocity - flow velocity blood viscosity  : by decreasing flow velocity by increasing hematocrit by increasing hematocrit

29 This is important at low flow velocity, mainly This is important at low flow velocity, mainly Why? Why? - Er aggregation (reversible) - Er aggregation (reversible) - platelet aggregation (irreversible ) - platelet aggregation (irreversible ) In the brain microcirculation (vascular bed distal to In the brain microcirculation (vascular bed distal to the of  m diameters, arterioles into the brain parenchyma) the of  m diameters, arterioles into the brain parenchyma) blood viscosity changes with changes of vessels blood viscosity changes with changes of vessels diameter, mainly diameter, mainly

30 Summary: Disturbancies of brain microcirculation accompanied Disturbancies of brain microcirculation accompanied by hemorheologic changes at low blood flow velocity by hemorheologic changes at low blood flow velocity are considered as important pathogenic factor are considered as important pathogenic factor promoting development of cerebral ischemia promoting development of cerebral ischemia and cerebral infarction and cerebral infarction Initially, as diameter of vessels falls, the blood Initially, as diameter of vessels falls, the blood viscosity falls, too. viscosity falls, too. When vessels diameter is reduced to less than When vessels diameter is reduced to less than 5-7  m, viscosity again increases (inversion 5-7  m, viscosity again increases (inversion phenomenon) phenomenon)

31 3. No - reflow phenomenon Definition: Impaired microcirculatory filling after temporary occlusion of cerebral artery temporary occlusion of cerebral artery Result: This mechanism can contribute to development of irreversibility of cell damage in ischemic region irreversibility of cell damage in ischemic region Summary: It can be disputed if no-reflow after transient focal ischemia at normal blood pressure is of focal ischemia at normal blood pressure is of pathogenic significance for infarct development pathogenic significance for infarct development or merely accompaniment of irreversible tissue or merely accompaniment of irreversible tissue injury injury

32 4. Changes in cerebral blood flow regulation cerebral ischemia  both CO 2 reactivity and cerebral ischemia  both CO 2 reactivity and autoregulation of cerebral autoregulation of cerebral vessels are disturbed vessels are disturbed In the center of ischemic territory: a)CO 2 reactivity – abolished or even reversed (i.e. blood flow may decrease with increasing PaCO 2 ) decrease with increasing PaCO 2 ) b) disturbance of autoregulation – mainly when BP is decreased local blood – mainly when BP is decreased local blood perfusion pressure is below the lower limit of the perfusion pressure is below the lower limit of the autoregulatory capacity of the cerebrovascular autoregulatory capacity of the cerebrovascular bed  vessels are maximally dilated bed  vessels are maximally dilated

33 These disturbances contribute to the phenomenon of These disturbances contribute to the phenomenon of post – ischemic hypoperfusion which is important post – ischemic hypoperfusion which is important pathophysiological mechanism for the development of pathophysiological mechanism for the development of secondary neuronal injury after global cerebral ischemia secondary neuronal injury after global cerebral ischemia Disturbancies of flow regulation  luxury perfusion luxury perfusion = oxygen supply to tissue exceeds the Disturbancies of flow regulation  luxury perfusion luxury perfusion = oxygen supply to tissue exceeds the oxygen requirements of the tissue oxygen requirements of the tissue Disturbances of flow regulation after stroke are longlasting: Disturbances of flow regulation after stroke are longlasting: - for autoregulation up to 30 days, - for autoregulation up to 30 days, - for CO 2 reactivity up to 12 days. - for CO 2 reactivity up to 12 days.

34 Possible mechanism involved: - vasoparalysis brought about by the release - vasoparalysis brought about by the release of acidic metabolites from the ischemic tissue of acidic metabolites from the ischemic tissue Forms of luxury perfusion: a) absolute (true hyperemia) a) absolute (true hyperemia) b) relative (depending on the level of O 2 consumption) b) relative (depending on the level of O 2 consumption)

35 5. Segmental vascular resistance - its importance fordevelopment CI fordevelopment CI Two different types of brain vessels have to be Two different types of brain vessels have to be distinguished : distinguished : a) extracerebral (conducting and superficial) vessels a) extracerebral (conducting and superficial) vessels - extracerebral segment of the vascular bad (a.carotis, a.basilaris,... and leptomeningeal anastomoses) a.basilaris,... and leptomeningeal anastomoses) b) nutrient (penetrating) vessels b) nutrient (penetrating) vessels - intracerebral segment of brain circulation (vessels penetrating to brain tissue and capillary network penetrating to brain tissue and capillary network supplied by them) supplied by them)

36 Both of segments are involved in autoregulation of blood flow through brain, but intracerebral segment react to CO 2, only Middle cerebral artery constriction  resistance of extracerebral conducting vessels  pial arterial BP   autoregulatory dilation of intracerebral vascular segment

37 6. Intracerebral steal phenomena (syndrome) The interconnection of ischemic and non-ischemic vascular territories The interconnection of ischemic and non-ischemic vascular territories by anastomotic channels may divert blood from one region to the by anastomotic channels may divert blood from one region to the other, depending on the magnitude and the direction of BP gradient other, depending on the magnitude and the direction of BP gradient across the anastomotic connections across the anastomotic connections The associated change of regional blood flow is called "steal„ if it results in The associated change of regional blood flow is called "steal„ if it results in a decrease of flow, or "inverse steal" if it results in a increase of flow a decrease of flow, or "inverse steal" if it results in a increase of flow (Robin Hood syndrome) in ischemic territories (Robin Hood syndrome) in ischemic territories Mechanism in steal phenomena occurence: vasodilation in non-ischemic brain regions (  pCO 2, anesthesia)  BP in vasodilation in non-ischemic brain regions (  pCO 2, anesthesia)  BP in pial arterial network  of the collateral blood supply to the ischemic pial arterial network  of the collateral blood supply to the ischemic territory territory

38 Summary: Despite of existing knowledge about steal and inverse steal phenomena, it is not possible to predict alterations of degree and extent of ischemia when blood flow in the non-ischemic territories is manipulated. Such manipulations are not recommended up to now for the treatment of stroke Mechanism of inverse steal phenomena: vasoconstriction (  pCO2) in the intact brain regions (or indirectly - to vasoconstriction (  pCO2) in the intact brain regions (or indirectly - to a decrease of intracranial pressure causing an improvement of blood a decrease of intracranial pressure causing an improvement of blood perfusion)   of blood flow in ischemic brain region perfusion)   of blood flow in ischemic brain region

39 7. Thresholds of ischemic injury In the intact brain metabolic rate can be considered In the intact brain metabolic rate can be considered as the sum of: as the sum of: a) activation metabolism - supports the spontaneous electrical activity electrical activity (synaptic transmission, generation of action potentials ) (synaptic transmission, generation of action potentials ) b) basal (residual) metabolism - supports the vital functions of the cell (ion homeostasis, osmoregulation, functions of the cell (ion homeostasis, osmoregulation, transport mechanisms, production of structural transport mechanisms, production of structural molecules) molecules)

40 1/3 of its energy for maintenance of synaptic transmission 1/3 for transport of Na + and K + 1/3 for preserving of structural integrity Gradual  of oxygen delivery   a) reversible disturbances of coordinating  a) reversible disturbances of coordinating and electrophysiological functions and electrophysiological functions b) irreversible structural damage occurs b) irreversible structural damage occurs Ischemic thresholds for functional and structural damage of brain due to ischemia are showed in scheme (Fig. 1) The working brain consumes about:

41 Thresholds of ischemia

42 Thresholds for functionall disturbances: a) the appearance of functional changes (clinical symptoms and signs) when focal blood flow rate was below 0.23 ml/g/min and signs) when focal blood flow rate was below 0.23 ml/g/min b) complete hemiplegia was present when blood flow rate decline to ml/g/min decline to ml/g/min c)threshold of the suppression of EEG activity begins at the flow rate 0.20ml/g/min and EEG became isoelectric when blood flow rate 0.20ml/g/min and EEG became isoelectric when blood flow rate is between ml/g/min rate is between ml/g/min d)depolarization of cell membranes occurs at flow levels below ml/g/min (sudden increase extracellular K + and ml/g/min (sudden increase extracellular K + and associated fall of extracellular Ca++ (threshold for ion pump associated fall of extracellular Ca++ (threshold for ion pump failure - it is the lower level of the penumbra range) failure - it is the lower level of the penumbra range)

43 Threshold for morphological injury Development of morphological lesions requires: a) minimal time (manifestation or maturation time) b) certain density of ischemia permanent ischemia ml/g/min  histological changes permanent ischemia ml/g/min  histological changes 2 hours ischemia 0.12 ml/g/min  histological changes 2 hours ischemia 0.12 ml/g/min  histological changes 1 hour ischemia ml/g/min  histological changes 1 hour ischemia ml/g/min  histological changes

44 8. The concept of ischemic penumbra The term penumbra was coined in analogy to the half- shaded The term penumbra was coined in analogy to the half- shaded zone around the center of a complete solar eclipse in order to zone around the center of a complete solar eclipse in order to describe the ring-like area of reduced flow around the more describe the ring-like area of reduced flow around the more densely ischemic center of an infarct densely ischemic center of an infarct In pathophysiological terms: it is the blood flow range between the thresholds of transmitters it is the blood flow range between the thresholds of transmitters release and cell membranes failure release and cell membranes failure So: functional activity of the neurons is suppressed although the metabolic acitivity for maintenance of structural integrity of the cell is still acitivity for maintenance of structural integrity of the cell is still preserved - neurons are injured but still viable preserved - neurons are injured but still viable Penumbra should be defined as a flow range between ml/g/min

45 Within the penumbra zone: Within the penumbra zone: - autoregulation of blood flow is disturbed - CO2 reactivity of blood vessels is partially preserved - ATP is almost normal - slight decrease of tissue glucose content (begining insufficiency of substrate availability) (begining insufficiency of substrate availability) Summary: Penumbra concept is important because it provides Penumbra concept is important because it provides a rational basis for functional improvements injured a rational basis for functional improvements injured brain tissue occuring long after the onset of stroke brain tissue occuring long after the onset of stroke

46 Úplná ischémia Hypoglycemia SD Penumbra Total ischemia The changes of Ca++ concentration intra- and extracellulary during different pathological brain processes

47 9. The concept of diaschisis Diaschisis = the term for remote disturbances of brain cells due to the suppression of neurons connected to due to the suppression of neurons connected to the injured (ischemic) region the injured (ischemic) region Possible mechanism involved in diaschisis occurence : the neurons in remote focus of brain from ischemic the neurons in remote focus of brain from ischemic injury suffer a kind of shock when they are deprived injury suffer a kind of shock when they are deprived from some of their afferent input comming from from some of their afferent input comming from ischemic focus ischemic focus

48 Time characteristic of diaschisis development diaschisis appears within 30 min after the onset of diaschisis appears within 30 min after the onset of ischemia ischemia reversal of the phenomena has been observed after a few month reversal of the phenomena has been observed after a few month it is reasonable to assume that deactivation of nerve fiber system it is reasonable to assume that deactivation of nerve fiber system connecting the areas involved causes a depresion of functional connecting the areas involved causes a depresion of functional activity because decrease of blood flow and metabolic rate are activity because decrease of blood flow and metabolic rate are coupled coupled a possible molecular mediator of diaschisis is a disturbed neurotransmitter metabolism a possible molecular mediator of diaschisis is a disturbed neurotransmitter metabolism

49 C. Consequences of cerebral ischemia Neurophysiological disturbances Neurophysiological disturbances a) neurological deficit (forced ambulation with circling, tonic deviation a) neurological deficit (forced ambulation with circling, tonic deviation of the head and neck toward the side of the occluded artery... active of the head and neck toward the side of the occluded artery... active movements cease  opposite limbs become weak, development of movements cease  opposite limbs become weak, development of apathetic or akinetic state apathetic or akinetic state b) suppresion of electrocortical activity c) suppresion of cortical evoked potentials

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53 2. Changes in ECF: a)changes in extracellular fluid content:  concentration of K +  concentration of Na +  concentration of Ca ++ b) changes in extracellular fluid volume: b) changes in extracellular fluid volume:  volume of ECF  volume of ECF Increase of the intracellular cytosolic calcium concentration is one of three major factors involved in ischemic brain damage. Other two factors are: acidosis and production of free radicals c) changes of Ca ++ – look at schematic diagrams illustrating changes c) changes of Ca ++ – look at schematic diagrams illustrating changes in Ca ++ concentration in extra- and intracellulary in Ca ++ concentration in extra- and intracellulary space space

54 3. Biochemical changes a) energy metabolism: a) energy metabolism: cerebral ischemia  first step: shortage of O 2 cerebral ischemia  first step: shortage of O 2  second step: shortage of glucose  second step: shortage of glucose Results:  NADH,  ATP and KP,  concentration of lactate  shortage Results:  NADH,  ATP and KP,  concentration of lactate  shortage of energy, acidosis of energy, acidosis b) lipid metabolism: b) lipid metabolism: -  intracellular Ca++  activation of membrane phospholipase A 2  -  intracellular Ca++  activation of membrane phospholipase A 2   release of poly-unsaturated fatty acids into intracellular  release of poly-unsaturated fatty acids into intracellular compartment compartment - activation of phospholipase C  arachidonic acid  PGL, LT, TBX - activation of phospholipase C  arachidonic acid  PGL, LT, TBX

55 c) neurotransmitter metabolism: - disturbances exist in synthesis, degradation, releasing and binding of - disturbances exist in synthesis, degradation, releasing and binding of neurotransmitters neurotransmitters With prolong or severe ischemia: With prolong or severe ischemia:  norepinephrine, serotonin, dopamin  norepinephrine, serotonin, dopamin  alanin and GABA (inhibitory neurotransmitters)  alanin and GABA (inhibitory neurotransmitters)  asparate and glutamate (excitatory neurotransmitters)  asparate and glutamate (excitatory neurotransmitters) d) protein synthesis: disturbances (  ) of protein synthesis  ihibition of reparating processes synthesis  ihibition of reparating processes

56 4. Ischemic brain edema Definition: Definition: It is the abnormal accumulation of fluid within the brain It is the abnormal accumulation of fluid within the brain parenchyma leading to the volumetric enlargement parenchyma leading to the volumetric enlargement of the tissue of the tissue a) by interfering with the water and electrolyte homeostasis of the tissue b) by its adverse effect on myelinated nerve fibers c) by its volumetric effect causing local compression of the microcirculation, rise intracranial pressure, dislocation of parts of the brain Brain edema aggravates the pathological process induced by ischemia Brain edema aggravates the pathological process induced by ischemia in different ways: in different ways:

57 Mechanisms involved in ischemic brain edema development I schemic brain edema has two phases: I schemic brain edema has two phases: 1) Initially is main mechanism damage of cells: 1) Initially is main mechanism damage of cells:  cytotoxic component - disturbances of cell volume regulation  intracellular  cytotoxic component - disturbances of cell volume regulation  intracellular edema (not major changes of the blood-brain barrier edema (not major changes of the blood-brain barrier permeability to macromolecules) permeability to macromolecules) 2) Later on: 2) Later on: vasogenic component: vasogenic component: - disruption of the blood - brain barrier to circulating - disruption of the blood - brain barrier to circulating macromolecules  extracellular edema macromolecules  extracellular edema

58 Ischemic preconditioning in the brain „What does't kill you makes you stronger“ - Preconditioning CSD applied 3 days before middle cerebral artery occlusion may increase the brain's resistance to focal ischemic damage and may be used as a model to explore the neuroprotective molecular responses of neuronal and glial cells (Matsushima et al., 1996)


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