pathophysiology of ischaemic stroke 4
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The oligaemia
Oligaemic tissue exists at a CBF range above the penumbra threshold and though it shows a mild
degree of misery perfusion (high OEF) on PE! it is not normally at ris" of infarction (Furlan et
al#! $%%&)# hus! misery perfusion should not be e'uated with penumbra in acute stro"e#
Cellular changes that occur in the oligaemic blood flow range in acute stro"e are limited to
differential induction and inhibition of protein synthesis# his li"ely represents the activation of a
cellular stress response in which heatshoc" proteins! unfolded proteins! endoplasmic reticulum
"inases! caspases and many others are involved (e*racia! +,,-)# Prolonged persistence of
cellular stress responses initiates apoptotic programmed cell death and hence may explain the
selective loss of neurons in areas remote from the penumbra and core of cerebral ischaemia
(Paschen and .engesdorf! +,,/)# Current therapeutic interventions do not specifically target the
oligaemic compartment! apart from prevention of secondary insults such as systemic hypotension
and hyperglycaemia which may threaten the oligaemia and incorporate it into the atris"
compartment (Baron! +,,$b)#
Secondary events and contributors
Imaging has been used to identify secondary contributors to ischaemic injury
and investigate their inuence on tissue outcome. Multi-modal MRI
constitutes the main tool in these studies because of its relative availability
and tolerability in the acute setting.
Hyperglycaemia
Parsons et al. (2002e!"lored the association of hy"erglycaemia #ith the
fate of at-ris$ hy"o"erfused tissue. %hey sho#ed that acute hy"erglycaemia
#as inde"endently correlated #ith reduced tissue survival and that higher
blood glucose levels #ere also strongly correlated #ith larger &nal infarct
si'es and #orse functional outcomes. urthermore) using "roton MR
s"ectrosco"y) they demonstrated that higher acute blood glucose in "atients
#ith *+I,P+I mismatch #as associated #ith greater lactate "roduction)
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#hich) in turn) #as inde"endently associated #ith the reduced salvage of
mismatched tissue. aird et al. (200similarly demonstrated that high
acute blood glucose levels #ere strongly correlated #ith infarct e!"ansion on
serial MRI and #ith #orsening of functional outcomes. It is) ho#ever) still not
certain if hy"erglycaemia is in itself detrimental in acute stro$e or that it israther a manifestation of a more fundamental and injurious "rocess such as
sym"athetic activation or hy"ercortisolism. %his is em"hasi'ed by the failure
of a large trial of intensive insulin thera"y to detect any functional bene&t
des"ite achieving sustained euglycaemia (/ray et al.) 200. 1et this trial had
a number of shortcomings. irst) "hysiological imaging #as not em"loyed in
selecting "atients the trial #as "rematurely terminated due to slo#
recruitment and a #ide range of "lasma glucose levels #ere considered
abnormal (3,43 mM and actively treated for a target ca"illary glucose of 6,
mM. %his may not have been an ade7uate goal) and given that glucose,
"otassium,insulin infusions also e8ected a signi&cant dro" in systemic blood
"ressure in the treatment grou") the results ought not be considered
de&nitive.
Haematocrit
9levated blood haematocrit has been sho#n to associate #ith infarct
e!"ansion and reduced "enumbral tissue salvage (:ll"ort et al.) 200;. %hese
e8ects are "robably mediated by increased blood viscosity and im"airment
of ca"illary o#. =.
Systemic blood pressure
*emonstration of high ?9 or *+I,P+I mismatch in the setting of acute
stro$e im"lies that autoregulation of @ is im"aired in the a8ected territory.
%hus) any lo#ering of the systemic arterial "ressure is li$ely to further reduce
the cerebral "erfusion "ressure and in turn the @ in the a8ected tissue)
#hich can be harmful for the "enumbra as #ell as the oligaemia.
:ccordingly) blood "ressure reductions in acute ischaemic stro$e have
fre7uently been associated #ith #orse outcome (:hmed et al.) 2000)
es"ecially #ith iatrogenic lo#ering of reactive hy"ertension. @onversely)
observing hy"er"erfusion) "articularly if early oedema is demonstrated by @%
or MRI) may "rovide rationale for treating hy"ertension as it is suggested
that hy"er"erfusion in necrotic tissue may "romote the develo"ment of
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malignant brain s#elling (Marchal et al.) 4===b. Aeveral trials are currently
under#ay to address these 7uestions and assess the o"timum management
of blood "ressure in the acute stage) including the BC-based @ontrolling
0 (Hahedi et al.) 200. %he reasons behind the
develo"ment of MMI are not clearly understood) but some evidence "oints to
factors beyond the si'e of infarction) such as inammation and blood,brain
barrier brea$do#n) as instrumental mechanisms (Aerena et al.) 200;.
Aubstantial vasogenic oedema increases local tissue "ressure and thus
reduces the e8ective "erfusion "ressure. %his) in turn) can lead the
"enumbra to "rogress to infarction and hence lead to further infarct
e!"ansion #ith develo"ment of more oedema and a vicious cycle ensues.
Predicting the develo"ment of MMI as early as "ossible is im"ortant to allo#
timely institution of thera"y. Imaging-based "redictors include occlusion of
the "ro!imal M@:) carotid % occlusion) involvement of both the su"er&cial
and dee" M@: territories) inade7uate circle of +illis and involvement of other
vascular territories (Jaramillo et al.) 2003. P9% and single "hoton emission
@% allo# accurate "rediction of MMI (Marchal et al.) 4==; errouschot et al.)
4==>) but the more clinically available *+I MRI is also of considerable
"otential. : large *+I lesion volume (K46; ml #ithin 46 h or K>2 ml #ithin 3h re"ortedly "redicts MMI #ith 400 sensitivity and =6 s"eci&city
(?""enheim et al.) 2000 %homalla et al.) 200.
:necdotal clinical re"orts of decom"ressive surgery for MMI "rom"ted
e!"erimental studies that demonstrated a bene&cial e8ect on infarct si'e
and outcome (orsting et al.) 4==;. 9ventually) several clinical trials have
sho#n that decom"ressive surgery) in the form of #ide hemicraniectomy and
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dura"lasty "erformed #ithin 6> h of stro$e onset reduces mortality by an
absolute ;0 and im"roves functional outcome in the survivors) although
less im"ressively (Hahedi et al.) 200. 9arly decom"ression "revents life-
threatening brain herniation and "robably also reduces the detrimental
e8ects of raised intracranial "ressure on tissue "erfusion "ressure. Inductionof moderate hy"othermia (around L@ has also been used in the treatment
of MMI and some small o"en studies sho#ed a bene&cial e8ect on clinical
outcome (Ach#ab et al.) 2004 *e /eorgia et al.) 2006) though carrying the
ris$s of "neumonia and rebound increase in intracranial "ressure on re-
#arming. ?n the other hand) osmotically active agents (for e!am"le)
mannitol and steroids o8er little bene&t in limiting the "rogression of MMI)
and hence devising novel "harmacological a""roaches to brain oedema
remains an area of "otential future develo"ment.
Infammation
Inammation is thought to contribute to the "atho"hysiology of neuronal cell
death by several mechanisms) including a"o"tosis (Price et al.) 200. +ithin
minutes of ischaemia) "roinammatory genes are u"regulated and adhesion
molecules are e!"ressed on the vascular endothelium. Feutro"hils then
migrate from the blood into the brain "arenchyma #ithin hours after
re"erfusion (9merich et al.) 2002) follo#ed by macro"hages and monocytes
#ithin a fe# days. %he vast majority of macro"hages in the infarct area
a""ear to be derived from local microglia that are activated before
macro"hage in<ration from the blood (Achilling et al.) 200) although the
tem"oral "attern is not entirely clear. :nimal studies suggest that microglial
activation also e!tends beyond the core and could contribute to "eri-infarct
neuronal death (Mabuchi et al.) 2000. @onversely) some evidence also e!ists
for a bene&cial or "rotective role for inammatory cell recruitment and
activation in the ischaemic "rocess (*anton and *ietrich) 200) including
"romotion of "lasticity and modulation of neurotro"hic factors (alancette-
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inammation. In general) the results of these studies agree that microglial
activation becomes signi&cant after a fe# days of stro$e and "ersists for over
0 days) #ith a "ea$ around 2 #ee$s from stro$e onset (Aette et al.)
4== /erhard et al.) 200; Price et al.) 2003. Fotably) the s"atial
distribution of PC444=; binding evolves to include not only the core but alsothe rescued "enumbra #here inammation may be secondary (or
contributes to selective neuronal damage (aron) 200;a. Increased
PC444=; binding may also be seen in brain regions distant from the infarct)
including the contralateral hemis"here) "ossibly re"resenting remote
+allerian degeneration (Pa""ata et al.) 2000. %hese &ndings suggest that
"otential targets for thera"y may still e!ist for #ee$s after stro$e onset. :
"aramagnetic MRI contrast agent (ultrasmall su"er"aramagnetic iron o!ide)
#hich is "rimarily ta$en u" by blood-derived macro"hages) has also been
used to demonstrate "arenchymal macro"hage in<ration in animals and
humans follo#ing ischaemic stro$e (Cleinschnit' et al.) 200 Aaleh et al.)
2006 +iart et al.) 200. %he e8ect #as "rominent in the second #ee$ after
stro$e and #as inde"endent of blood,brain barrier disru"tion and lesion si'e
(Fighoghossian et al.) 200. PC444=; and ultrasmall su"er"aramagnetic
iron o!ide thus target t#o "otentially overla""ing com"onents of the brain
inammatory res"onse and further #or$ using these t#o attractive
techni7ues can be e!"ected to e!"and the understanding of inammation in
stro$e and guide thera"eutic innovation.
Conclusions
Physiological imaging has elucidated many of the fundamental "rocesses of
ischaemic brain injury and demonstrated the substantial heterogeneity
among individual stro$e "atients. %he "rolonged "ersistence of salvageable
"enumbral tissue has been established) and several other "otential targets
for intervention are gradually emerging. In future trials of thera"eutic agents)
the use of "hysiological imaging to select the "atient category that best
matches the drugGs "resumed mode of action is recommended) rather thanlum"ing together "atients #ith entirely di8erent "atho"hysiological "atterns
in the so-called Dlarge trialsG) #hich have all failed so far. %his a""roach
"romises to bring about further signi&cant advances in the treatment of
ischaemic stro$e. urthermore) imaging has also highlighted the im"ortant
roles of the brain vasculature) glia and su""orting matri! in stro$e) all of
#hich re"resent "otential targets for thera"y beyond neuro"rotectionper se.
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Glossary
@ cerebral blood o#
@H cerebral blood volume
*+I di8usion-#eighted imaging
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?9 o!ygen e!traction fraction
P9% "ositron emission tomogra"hy
P+I "erfusion-#eighted imaging
BAPI?
ultrasmall su"er"aramagnetic irono!ide