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PATHOPHYSIOLOGY OF CEREBRAL ISCHEMIA. Prof. J. HANACEK , M.D., Ph.D. Anatomy of brain vessels. Carotic and vertebral arteries. View to medulla, brainstem and inferior brain vessels. Brain arteries - anterior and posterior circulation. Brain arteries – lateral view.

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PATHOPHYSIOLOGY OF CEREBRAL ISCHEMIA


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pathophysiology of cerebral ischemia

PATHOPHYSIOLOGY OF CEREBRAL ISCHEMIA

Prof. J. HANACEK, M.D., Ph.D.

slide8

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

slide14

Microaneurysms

in penetrating

arteries

slide16

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)

slide17

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)

slide18

Cardiac sources

of cerebral emboli

slide19

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

slide20

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

slide21

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

slide22

Types of ischemic

and hemorrhagic

stroke

slide23

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

slide24

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

slide25

Úplná ischémia

Hypoglycemia

Total ischemia

exc

inc

Ischemia

Penumbra

SD

Intra- and extracellularchanges of Ca++

slide26

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)
slide27

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:

slide28

•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

slide29

•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

slide30

•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

slide31

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

slide32

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

slide33

•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

slide34

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)

slide35

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)

slide36

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

slide37

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

slide38

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

slide39

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)

slide40

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)

slide42

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)
slide43

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

slide44

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

slide45

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

slide46

Úplná ischémia

Hypoglycemia

Total ischemia

Penumbra

SD

The changes of Ca++ concentration intra- and extracellulary

during different pathological brain processes

slide47

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

slide48

•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

slide49

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

slide53

2.Changes in ECF:

  • changes in extracellular fluid content:
  •  concentration of K+concentration of Na+
  •  concentration of Ca ++

b) changes in extracellular fluid volume:

volume of ECF

c) changes of Ca++–look at schematic diagrams illustrating changes

in Ca++ concentration inextra- and intracellulary

space

Increaseof the intracellular cytosoliccalciumconcentration is one

of three majorfactors involved in ischemicbrain damage.

Other two factors are: acidosis and production of freeradicals

slide54

3.Biochemical changes

a)energy metabolism:

cerebral ischemia first step: shortage of O2

second step: shortage of glucose

Results:NADH, ATP and KP,  concentration of lactate shortage

of energy, acidosis

b)lipid metabolism:

-  intracellular Ca++ activation of membranephospholipase A2

 release of poly-unsaturated fattyacids into intracellular

compartment

-activation of phospholipase C  arachidonic acid PGL, LT, TBX

slide55

c)neurotransmitter metabolism:

- disturbances exist in synthesis, degradation, releasingand bindingof

neurotransmitters

With prolong or severe ischemia:

norepinephrine, serotonin, dopamin

 alanin and GABA (inhibitory neurotransmitters)

asparate and glutamate (excitatory neurotransmitters)

d)protein synthesis: disturbances ( )of protein

synthesis ihibition of reparating processes

slide56

4.Ischemic brain edema

Definition:

It is the abnormal accumulation of fluid within the brain

parenchyma leading to the volumetric enlargement

of the tissue

Brain edema aggravates the pathological process induced by ischemia

in different ways:

a) by interfering with the water and electrolyte homeostasisof the tissue

b) by its adverse effect on myelinated nerve fibers

c) by its volumetric effect causing local compression of themicrocirculation, rise intracranial pressure, dislocationof parts of the brain

slide57

Mechanisms involved in ischemic brain edema

development

Ischemic brain edema has two phases:

1) Initially is main mechanism damage of cells:

 cytotoxic component- disturbances of cell volume regulation intracellular

edema(not major changesof theblood-brain barrier

permeability to macromolecules)

2)Later on:

•vasogenic component:

- disruptionof the blood - brain barrier to circulating

macromolecules extracellular edema

slide58

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)