pathophysiology of ischaemic stroke 2

7/25/2019 Pathophysiology of Ischaemic Stroke 2

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Basic concepts

Most experimental and clinical research have focused on proximal occlusion

of the middle cerebral artery (MCA). Interruption of blood ow to the supplied

basal ganglia white matter and cortex causes a gradient of hypoperfusion toemerge (!igure ") rather than complete and homogeneous ischaemia of the

entire MCA territory (Astrup et al. "#$"). %egions su&ering the most severe

degrees of hypoperfusion rapidly progress to irreversible damage

representing the 'ischaemic core. n multi*tracer "+ ,- this tissue exhibits

very low cerebral blood ow (C/!) cerebral blood volume (C/0) and

metabolic rates of oxygen and glucose (Marchal et al. "###a). he remaining

hypoperfused tissue exhibits impairment of the normal blood ow

autoregulatory mechanisms and is pathophysiologically divided relative to a

well*de1ned perfusion threshold into two compartments namely the'penumbra and 'oligaemia. In the penumbra oxygen metabolism is

preserved relative to C/! the oxygen extraction fraction (-!) is elevated

(severe 'misery perfusion) and the C/0 is normal or elevated. issue within

the penumbra is potentially salvageable yet its extent decreases over time

by gradual recruitment into the core and as such represents a 2ey target for

therapeutic intervention (/aron et al. "##+). his course of events varies

from patient to patient but most exhibit substantial volumes of penumbra

for many hours (/aron "###) or exceptionally days after stro2e onset

(,ere3 et al. 4556). he oligaemic compartment on the other hand su&ers a

milder degree of hypoperfusion with normal oxygen consumption and

elevated C/0 and -! and is not normally at ris2 of infarction. If the

occlusion persists however secondary events such as systemic hypotension

intracranial hypertension or hyperglycaemia may topple this delicate balance

and force the oligaemia into a penumbral state and eventually recruitment

into the necrotic core.

The ischaemic core

he ischaemic core is by de1nition beyond therapeutic rescue. It is

electrically silent and its volume is highly correlated to and explains part of

the severity of admission neurological de1cit (Marchal et al. "###a). n the

cellular level irreversible damage is heralded by depletion of energy

metabolites and failure of the cell membrane to maintain its physiologic

gradients with dramatic disruption of ion and water homoeostasis (Moustafa

and /aron 4557). his manifests as massive e8ux of 9:and reciprocal inux
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of ;a: water and Ca::with conse


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penumbral tissue. his has also recently been further con1rmed in human

,-*M% studies (uadagno et al. 4556).

The core as a therapeutic target

Hithin the necrotic core the vasculature may also be severely damagedexposing it to the ris2 of undergoing haemorrhagic transformation (>). his

is especially the case with extensive infarction and with the use of

thrombolytics potentially causing further worsening of the clinical condition

and outcome and therefore outweighing the bene1t of salvaging the

ischaemic penumbra (!iehler et al. 455+). hus although the core is

essentially not recoverable prediction and prevention of > within it

represent important therapeutic goals. !or instance new thrombolytic agents

that do not interfere with endothelial function or induce matrix

metalloproteinase dysregulation (Hanget al

. 455@) might reduce theincidence of thrombolysis*associated haemorrhage. More generally vascular

protectants and agents that modulate matrix proteolysis may also be

bene1cial in preventing > within the infarct (Lee et al. 455@).

In clinical trials > is often divided into grades based on radiologic

appearance into small or conuent petechiae within the infarction (>I*" and

>I*4 respectively)= parenchymal haematoma occupying NE5O of the

infarcted area with a mild space*occupying e&ect (,>*") and parenchymal

haematoma in PE5O of the infarcted area with a signi1cant space*occupying

e&ect (,>*4) (Larrue et al. 455"). hese are further remains to be proven but early reperfusion with

inury to the microvasculature and disruption of the bloodBbrain barrier has

been suggested. Indeed some studies (Latour et al. 455@=Harach and

Latour 455@) have used delayed gadolinium enhancement of cerebrospinal

uid space on M% uid*attenuated inversion recovery images as a mar2er of

bloodBbrain barrier disruption and demonstrated its dependency on

reperfusion and its association to > and worse clinical outcomes. It is still

not entirely clear however if these mar2ers will be useful in clinical decision*ma2ing or in the development of new therapeutic strategies for >.

A large parenchymal hypodensity on acute C statistically predicts the ris2 of

thrombolysis*associated haemorrhage hence the widespread notion of

withholding this treatment if hypodensity exceeds one*third of the MCA

territory (>ac2e et al. "##$). ?tudies using M%I have shown that areas of >
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have signi1cantly lower apparent di&usion coeJcient C/! and C/0 than

other areas with perfusion abnormality on initial imaging and that

reperfusion occurs in almost all cases showing > (?elim et al.

4554= Alsop et al. 455+). ;onetheless the results of these studies were not

analysed separately for symptomatic and asymptomatic grades of > andthe relevance of these associations to clinical outcome is not

identi1ed. Lansberg et al. (4557a)investigated predictors of any

haemorrhage causing symptomatic deterioration and found only a large GHI

lesion to be an independent predictor in multivariate analysis. homalla et al.

(4557)further argue that the > is merely a fre

pathophysiology of ischaemic stroke 2

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