pathophysiology of ischaemic stroke 3

7/25/2019 Pathophysiology of Ischaemic Stroke 3

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The ischaemic penumbra

The penumbra was originally described on electrophysiological basis as the

tissue existing between the thresholds of electrical failure and ion pump

failure (Astrup et al., 1981). Thereafter, a haemodynamic and metabolicapproach based on multitracer 1!" #$T has de%ned it as tissue that exists

between the threshold of infarction and the penumbral threshold (&aron,

'1a). "perationally, penumbral tissue must satisfy criteria of being (i)

functionally impaired iable hypoperfused tissue with undetermined fate that

is atris* of infarction if not salaged+ (ii) contributing to the clinical de%cit

and that (iii) its resolution is associated with proportional recoery of

neurologic function.

sing multitracer #$T, substantial olumes of cortical penumbra hae been

reported to decline oer time, being present in oer !- of the patientsstudied within 9 h, and in about onethird of the patients studied between !

and 18 h (/ise et al., 1980+ eiss, 199'+ 2archal et al., 1993). This con%rms

that the temporal window of opportunity for therapy is protracted in some

patients, but is rapidly shrin*ing in others, thus emphasi4ing the urgency of

acute stro*e management. 5ome patients deelop an extensie necrotic

infarct core within a few hours of stro*e onset, whereas spontaneous

reperfusion is seen in the remaining subgroup (2archal et al., 1990).

The demise of the penumbra is signalled by a decline in cerebral metabolic

rate of oxygen, with further decline or stabili4ation of the 6&7 (/ise et al.,

1980+ eiss, 199'+ 2archal et al., 1993) and a dramatic fall in the "$7, from

initially ery high to sometimes exceedingly low alues heralding the

exhaustion of the tissues oxygen needs. $arly reperfusion can reerse this

grim outcome as shown in studies in baboons (Tou4ani et al., 199!, 199)

and humans (eiss et al., 1998), reporting that large olumes of tissue with

penumbral leels of 6&7 escape necrosis if arterial recanali4ation is

achieed. Ample eidence from 1!" (7urlan et al., 1993+ eiss et al., 1998)

and 187:uoromisonida4ole #$T studies (;ead et al., '+ 2ar*uset al., 'ess predictably, a

better correlation also exists with 'month recoery scores, suggesting that

surial of the penumbra also in:uences late recoery, possibly through

allowing subse=uent periinfarct neuronal reorgani4ation (7urlan et al., 1993).
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%ndings are generally consistent with other techni=ues (2uir et al., '3a).

#erfusion computed tomography has attracted special interest as it is similar

in principle to 2; #/? but has the practical adantage of being more widely

aailable and cheaper than 2;. ;ecent studies on perfusion computed

tomography in acute stro*e demonstrated that tissue with 6& J' ml 1gK1represents the core, while a relatie mean transit time aboe 1

normal hemisphere with 6& B' ml 1 gK1best outlines atris* tissue

(/intermar* et al., '3). #erfusion computed tomography parameters

correlate ery well with 2; @/?F#/? and accurately predict %nal infarct

olume and clinical recoery, corroborating its potential utility in selecting

patients for thrombolysis ($astwood et al., '0+ 2uir et al.,

'3b+ /intermar*et al., ') een when the time of onset is not clear

(ellier et al., '3).

The penumbra as a therapeutic target

Reperfusion therapy in the 3-h window

?n the mid199s, recombinant tissue plasminogen actiator (alteplase)

emerged as the %rst eLectie therapy aimed at rescuing atris* tissue in the

%rst hours of stro*e. >arge trials demonstrated that ? recombinant tissue

plasminogen actiator therapy aLords at least a 0- increase in the

li*elihood of a good outcome when administered within 0 h, yet carries a 3F

- ris* of symptomatic intracranial haemorrhage (ac*e et al., '


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pathophysiological model outlined earlier suggests that reperfusion can be

bene%cial beyond 0 h through salage of the penumbra in appropriate

patients. $xtension of the therapeutic window is thus an attractie goal that

is currently being pursued cautiously with the use of physiologic imaging.

The @iLusion and perfusion imaging $aluation for nderstanding 5tro*e$olution study demonstrated a better clinical response among patients with

small @/? lesion and substantial 2; mismatch treated with alteplase

between 0 and 3 h, than in other subgroups, including the matched @/?F#/?

lesion, the small @/? and #/? lesion and the large @/? lesion subgroups

(Albers et al., '3). Thus, this important study highlighted the importance

of considering not only the presence of @/?F#/? mismatch but also the si4e

of the @/? lesion in the decisionma*ing process. The ongoing $#?T$T trial

further addresses this =uestion by randomi4ing patients to alteplase or

placebo 0F3 h after stro*e onset regardless of baseline 2;? %ndings, testingthe hypothesis that in retrospectie analysis patients with mismatch will

hae deried greater bene%t than those without (&utcher et al., '!).

5tudies comparing 2;?based alteplase treatment within 0F3 h to

conentional 6Tbased treatment within 0 h hae demonstrated similar

recanali4ation rates and functional outcomes (;other et al., ''+ ;ibo et al.,

'!). 2oreoer, 2;?based treatment in the F3 h time frame also shows

similar or superior safety and eNcacy to 6Tbased treatment within 0 h, when

compared directly (Gohrmann et al., '3) or to data from metaanalyses

(Thomalla et al., '3). #reliminary %ndings from pooling of results from1'1 patients further strengthen these conclusions (5chellinger et al., ').

2;based selection has also been used in studies testing the new

thrombolytic agent desmoteplase (ac*e et al., '!), where the presence of

2; @/?F#/? mismatch of '- or higher was used to select patients for

thrombolysis in the 0F9 h window. A more faourable clinical outcome was

demonstrated in patients who experienced reperfusion than in those who did

not (!'.! s '


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of the trial (nO3 in each group) may hae also contributed to the lac* of a

detectable bene%t oer placebo. #rouro*inase is another thrombolytic agent

that has been inestigated for use in acute stro*e. The #;"A6T ?? study used

catheter angiography and plain 6T to select patients with 26A occlusion for

intraarterial prouro*inase treatment up to 3 h from onset (7urlan et al.,1999). The %ndings were strongly in faour of a bene%cial eLect on clinical

outcome, and subse=uently it was shown that detailed analysis of the

patients 6T scans (ill et al., '0) may further improe patient selection for

this treatment. "ther thrombolytic agents (such as tenecteplase) and other

intraarterial reperfusion techni=ues are also under inestigation in acute

stro*e and imaging is increasingly being used to monitor their therapeutic

eLects (2olina and 5aer, '!).

Neuroprotection

/hen tested in humans, neuroprotectie agents designed to limit the demise

of atris* tissue hae consistently failed to produce the eLects obsered in

animal studies (5ait4 and 7isher, '+ 5huaib et al., '). These agents

targeted critical interlin*ed eents that occur in ischaemic tissue before or

after reperfusion ending in necrotic cell death (the Iischaemic cascade).

Their failure is ariously attributed, among many possibilities, to inade=uate

preclinical data or therapeutic targets, and the choice of ineLectie

compounds (Preen, ''). ?mportantly, physiologic imaging has only been

employed in ery few of these trials (for example, /arach et al., '), so

the grouping together of patient populations who may not een hae the

substrates targeted by such therapies (for example, penumbra) is another

li*ely factor for the failure of translation to humans.

A further reason that is proposed is that most neuroprotectie drugs were

designed to speci%cally reduce damage to the cortical grey matter rather

than the white matter (@ewar et al., 1999). 5eeral studies using #$T and

2;? hae demonstrated that substantial olumes of potentially salageable

tissue existed in white matter seeral hours after onset of stro*e and that it

is at least as resistant to ischaemia as grey matter (7alcaoet al.,

'


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Another potential strategy for neuroprotection is prehospital administration

of treatment that can essentially Ibuy time until imaging can be underta*en

and de%nitie therapy instituted. 5uch a neuroprotectant clearly has to be

safe and tolerable in both ischaemic and haemorrhagic stro*es, and should

be simple to administer by ambulance personnel. 2agnesium sulphate is onesuch candidate and is currently being tested within ' h of stro*e onset in a

large clinical trial (5aer et al., '


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#romising results also exist from small clinical trials. ?n one pilot study

(5inghal et al., '!a), 2;? @/?F#/? mismatch was used to select acute

stro*e patients to receie either 1- oxygen or room air for 8 h. "xygen

treated patients improed clinically during therapy and at '< h, with smaller

2; @/? lesions than in control subMects. 2oreoer, oxygen therapy wasassociated with an increase in relatie 6&7 and 6& within the perfusion

(mean transit time) abnormality, consistent with earlier obserations of a

asodilatory response to hyperoxia in ischaemic brain tissue rather than the

asoconstriction induced in normal brain tissue (Ea*aMima et al., 1980).

Another small trial (6hiu et al., '3) did not use an imaging end point but

showed that arger trials using similar

methodologies and physiological imaging are awaited.
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pathophysiology of ischaemic stroke 3

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