PATHOPHYSIOLOGY OF CEREBRAL ISCHEMIA

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 inducedby decreasing or suspending substrate delivery (oxygen and glucose) to the brain due to disturbaces of brainvessels 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 - 0.8 ml/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) 2. stenosis of cerebral artery +decreasing of systemic blood pressure 3. tromboembolism of large brain vessels 4. decreased cardiac output(due to decreased myocardial contractility, massive hemorrhage, others)

18. Cardiac sources of cerebral emboli

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

20. The richanastomoticconnections between thecarotid and vertebralarteries provide a powerfull collateral system whichisable tocompensatefor the occlusion of up to three of these arteries (known from animal experiment) • The good collateral system results in lesserischemic area than is a territory supplied by occluded artery • The bad collateral system results in ischemic area equal toa territory supplied by ocluded artery

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

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. Cosequences of brain ischemia Energy failure / depolarisation Transmitter release and receptor activation Ca2+ (DAG PKC) Lipolysis Protein phosphorylation Proteolysis Disaggregation of microtubuli Breakdown of cytoskeleton Enzyme conversion (FFAs.LPLs) Damage to membrane structure and function Dysfunction of receptors and ion channels Free radical formation Inhibition of axonal transport, blebbing

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

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 ofthe 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 cerebralartery • 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. Q = flow rate P = pressure gradient r = radius of tube l = length of the tube  = viscosity of the fluid P. r4 Q =  . 8 .l 2.Hemorheology and microcirculation - their importance in development CI Relationship between bloodviscosity and microcirculation:

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

29. •This is important at low flow velocity, mainly Why? -  Er aggregation (reversible) -  platelet aggregation (irreversible) •In the brain microcirculation(vascular bed distal to the of 30 -70m diameters, arterioles into thebrain parenchyma) blood viscositychanges withchanges of vessels diameter,mainly

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

31. 3.No-reflow phenomenon Definition:Impaired microcirculatory filling after temporary occlusion ofcerebral artery Result:This mechanism can contribute to development of irreversibilityof cell damage in ischemic region Summary:It can be disputed if no-reflow after transient focalischemia atnormal blood pressure is of pathogenic significance for infarctdevelopment or merelyaccompaniment of irreversible tissue injury

32. 4.Changes in cerebral blood flow regulation • cerebral ischemiaboth CO2 reactivity and autoregulation of cerebral vesselsare disturbed In the center of ischemic territory: • CO2 reactivity – abolished or even reversed(i.e. blood flow may • decrease with increasing PaCO2) b)disturbance of autoregulation –mainly when BP is decreasedlocalblood perfusion pressure is below the lower limit of the autoregulatory capacity of the cerebrovascular bed vesselsare maximally dilated

33. •Disturbances of flow regulation after stroke are longlasting: - forautoregulation up to 30 days, - for CO2 reactivity up to 12 days. •These disturbances contribute to the phenomenon of post– ischemichypoperfusion which is important pathophysiologicalmechanism for thedevelopment of secondary neuronal injury after global cerebral ischemia •Disturbancies of flow regulation luxury perfusion luxury perfusion = oxygen supply to tissue exceeds the oxygenrequirements of the tissue

34. Possible mechanism involved: - vasoparalysis brought about by the release ofacidic metabolites from the ischemic tissue Forms of luxury perfusion: a)  absolute (true hyperemia) b)  relative (depending on the level of O2 consumption)

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

36. Both of segmentsare involved in autoregulation of blood flowthrough brain, but intracerebral segmentreact to CO2, only Middle cerebral artery constriction resistance of extracerebralconducting vessels pial arterial BP autoregulatory dilation ofintracerebral vascular segment

37. 6.Intracerebral steal phenomena (syndrome) •The interconnection of ischemic and non-ischemicvascular territories by anastomotic channelsmay divertblood from one region to the other, depending on the magnitude and the directionof BP gradient across theanastomotic connections •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 (Robin Hood syndrome) in ischemic territories Mechanism in steal phenomena occurence: •vasodilation in non-ischemic brain regions (pCO2, anesthesia) BP in pial arterial network of the collateral bloodsupply to the ischemic territory

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

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

40. The working brain consumes about: 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 and electrophysiological functions b) irreversible structural damage occurs Ischemic thresholds for functional and structural damage of brain due to ischemia areshowed in scheme (Fig. 1)

41. Thresholds of ischemia

42. Thresholds for functionall disturbances: a) the appearance of functional changes (clinical symptoms andsigns) when focal blood flow rate was below0.23 ml/g/min b)complete hemiplegia was present when blood flow rate decline to0.08 - 0.09 ml/g/min • threshold of the suppression of EEG activity begins at the flow • rate0.20ml/g/min and EEG became isoelectric when blood flow • rate isbetween 0.15-0.16 ml/g/min • depolarization of cell membranes occurs at flow levels below • 0.08 -0.10 ml/g/min (sudden increase extracellular K+ and • associated fallof extracellular Ca++ (threshold for ion pump • failure - it is the lowerlevel 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 0.17 - 0.18 ml/g/minhistological changes •2 hours ischemia 0.12 ml/g/min histological changes •1 hour ischemia 0.05 - 0.06 ml/g/min histological changes

44. 8.The concept of ischemic penumbra The termpenumbrawas coined in analogy to the half-shaded zonearoundthe center of a complete solar eclipsein order to describe thering-likearea of reduced flowaround the more densely ischemic center of aninfarct In pathophysiological terms: •it is the bloodflow range between thethresholds of transmitters release and cell membranes failure So: functional activity of the neurons is suppressed although themetabolic acitivity for maintenance of structural integrity of the cell is still preserved - neurons are injured but stillviable Penumbra should be defined as a flow range between 0.10 - 0.23 ml/g/min

45. 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 ofsubstrate availability) Summary: Penumbra concept is important because it provides a rational basis for functional improvements injured brain tissue occuring long after the onset of stroke

46. Úplná ischémia Hypoglycemia Total ischemia Penumbra SD 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 ofneurons connected to the injured(ischemic) region Possible mechanism involved in diaschisis occurence: •the neurons in remote focus of brain from ischemic injury suffer akind of shock when they are deprived from some of their afferentinput comming from ischemic focus

48. •it is reasonable to assume that deactivation of nerve fiber system connectingthe areas involved causes a depresionof functional activitybecausedecrease of blood flow and metabolic rate are coupled •a possible molecular mediator of diaschisis is a disturbedneurotransmitter metabolism Time characteristic of diaschisis development •diaschisisappears within 30 min after the onset of ischemia •reversal of the phenomena has been observed after a few month

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