[Handbook of Clinical Neurology] Stroke Volume 92 || Chapter 4 Cerebral blood flow and the ischemic penumbra

Handbook of Clinical Neurology, Vol. 92 (3rd series)Stroke, Part IM. Fisher, Editor# 2009 Elsevier B.V. All rights reserved

Chapter 4

Cerebral blood flow and the ischemic penumbra

KONSTANTIN-A. HOSSMANN1* AND RICHARD J. TRAYSTMAN2

1Max-Planck-Institute for Neurological Research, Cologne, Germany2University of Colorado at Denver and Health Sciences Center, Aurora, CO, USA

4.1. Normal values of cerebral blood flow

In middle-aged healthy humans, mean resting blood

flow is between 0.45 and 0.60 ml/g/min (Sokoloff

et al., 1957; Cohen et al., 1967; Slosman et al., 2001).

Partial volume-corrected blood flow of cortical gray

matter structures is 0.60–1.00 ml/g/min while white

matter blood flow is around 0.20 ml/g/min or lower

(Law et al., 2000; Meltzer et al., 2000). These values

for gray and white matter correspond to a mean transit

time of the circulating blood of about 3.0 and 6.0 sec-

onds respectively. In young children, blood flow is

twice as high as in adults (Kennedy and Sokoloff,

1957), probably resulting from an elevated brain meta-

bolism in the young, whereas there is a small decline

in blood flow with age that may be dependent upon

density of neurons per unit of tissue volume (Brody,

1955). Similarly, cerebral blood flow in laboratory ani-

mals varies with neuronal density and is highest in

small rodents, such as gerbils, rats, and mice, and lower

in other species, but this depends upon age and anesthe-

sia (Table 4.1).

Anesthesia, hypothermia, and metabolic inhibitors

reduce blood flow to a variable degree depending on

the kind and extent of intervention. Using barbiturates

as an anesthetic agent, the dose-dependent reduction in

blood flow correlates with the amplitude of sponta-

neous electroencephalogram (EEG) activity and results

in a decline in blood flow by about 50%, at which time

EEG becomes isoelectric (Michenfelder and Milde,

1975). However, reduction in blood flow with barbitu-

rates is not uniform throughout brain, with reduced

blood flow being greatest in brain areas with the

highest resting blood flow in the unanesthetized

state (Landau et al., 1955). Since brain blood flow,

*Correspondence to: K.-A. Hossmann, Max-Planck-Institut fur N

Germany. E-mail: [email protected]

metabolism, and function are closely coupled, it would

appear that, in the awake state, about one-half of the

resting blood flow is required to support the basic

metabolic needs of the brain whereas the other half is

required to fuel the spontaneous electrical activity of

the neuropil.

4.2. Blood flow changes after focal vascularocclusion

Extent and density of ischemia following focal vascu-

lar occlusion depend on many factors, notably anato-

mical site of vascular obstruction, local blood

perfusion pressure, blood viscosity and degree of

microvascular involvement, collateral blood supply,

and segmental resistance of conductance vessels

within the ischemic territory. The brain artery most

frequently affected under both clinical and experimen-

tal conditions is the middle cerebral artery, which sup-

plies roughly 60% of the ipsilateral hemisphere

(Fig. 4.1). The proximal branches of this artery, the

lenticulostriate arteries, supply the basal ganglia and

are end arteries, whereas more distal branches, which

support the circulation of cerebral cortex, make collat-

eral connections with the leptomeningeal network of

Heubner’s anastomoses (see below). Proximal

occlusion of the middle cerebral artery therefore con-

sistently produces infarction in basal ganglia and a

variable degree of ischemia in the cerebral cortex,

depending on the efficacy of the collateral blood

supply. After distal occlusion of the middle cerebral

artery, the basal ganglia are spared and cortical ische-

mia depends on the status of the collateral system.

The less frequent occlusions of the anterior and

posterior cerebral arteries produce mainly cortical

eurologische Forschung, Gleuelerstrasse 50, D-5093 Koln,

mailto:[email protected]

Table 4.1

Cerebral blood flow values in laboratory animals

Species Blood flow (ml/g/min) Anesthesia Reference

Mouse 0.20 Isoflurane Foley et al., 2005

Rat Newborn (3–5 days) 0.36 Isoflurane Fumagalli et al., 2004

Newborn (7 days) 0.40 Isoflurane Vannucci et al., 2001

Adult 1.16 Awake Horinaka et al., 1997

Adult—cortex 1.19 Awake Sakurada et al., 1978

White matter 0.32 Awake Sakurada et al., 1978

Gerbil 0.81 Halothane Mies et al., 1990

0.54 Pentobarbital Turcani and Tureani, 2001

Rabbit Adult 0.40 Pentobarbital Littleton-Kearney et al.,

2000

0.56 Halothane/propofol Cenic et al., 2000

1.21 Awake Csete and Papp, 2000

Cat Adult cortex 1.30 Awake Sakurada et al., 1978

White matter 0.23 Awake Sakurada et al., 1978

0.44 Pentobarbital/halothane Rebel et al., 2003

1.00 Halothane Miyabe et al., 1996

0.30 Pentobarbital Schuier and Hossmann,

1980

Dog Newborn (2–7 days) 0.30 Halothane/nitrous oxide Mujsce et al., 1989

Adult—total brain 0.48 Awake Gross et al., 1980

White matter 0.19 Awake Gross et al., 1980

Adult—total 0.36 Pentobarbital McPherson et al., 1988

White matter 0.20 Pentobarbital McPherson et al., 1988

Sheep Preterm (93 day) 0.13 Awake Gleason et al., 2002

Near term (132 day) 0.20 Awake Gleason et al., 2002

Newborn lambs 1.00 Awake Jones and Traystman, 1984

Newborn lambs 0.60 Pentobarbital Miyabe et al., 1989

Adult 0.65 Awake Jones and Traystman, 1984

Pig Piglet (1–2 weeks) 0.48 Pentobarbital Ichord et al., 2001

Adult (4–6 weeks) 0.54 Pentobarbital Voelckel et al., 2002

Mini-pig 0.49 Isoflurane Andersen et al., 2005

Mini-pig (5–6 months) 0.55 Pentobarbital Delp et al., 2001

Monkey Young Rhesus (6 years) 0.55 Awake Noda et al., 2002

Old Rhesus (21 years) 0.43 Awake Noda et al., 2002

Adult monkey 0.26 Isoflurane Joshi et al., 2003

Adolescent baboon:

Total brain 0.75 Awake Meyer et al., 1980

White matter 0.35 Awake Meyer et al., 1980

Adolescent baboon 0.29 Etomidate/fentanyl Schumann-Bard et al., 2005

Adult baboon 0.55 Ketamine/nitrous oxide Kaufman et al., 2003

68 K.-A. HOSSMANN AND R.J. TRAYSTMAN

ischemia with a gradient of flow values, which

declines from the peripheral to more central parts of

the corresponding vascular territories.

Reversal of vascular occlusion initiates a triphasic

blood flow response, the dynamics of which depend

mainly on the duration of ischemia and the initial

reperfusion pressure. After ischemia times up to about

30 min, at normal blood pressure, tissue is reperfused

at increased blood flow rate (post-ischemic hyperemia

or luxury reperfusion), followed, after an interval that

roughly corresponds to the duration of the preceding

ischemia, by a reduction of blood flow below normal

(post-ischemic hypoperfusion). Finally, blood flow

increases again and stabilizes at or close to control

values. Post-ischemic hyperemia has been attributed

to release of vasoactive metabolites from injured brain

in combination with the post-ischemic loss of cerebro-

vascular regulation (Sundt and Waltz, 1971). The

Fig. 4.1. Autoradiographic measurements of cerebral blood flow in different experimental models of focal ischemia.

CCA, common carotid artery; MCA, middle cerebral artery. (Courtesy of G. Mies.)

CEREBRAL BLOOD FLOW AND THE ISCHEMIC PENUMBRA 69

hyperemic response may also be due, in part, to neuro-

genic vasodilator mechanisms (Macfarlane et al.,

1991). Post-ischemic cerebral metabolic depression,

along with microvascular obstruction may account

for post-ischemic hypoperfusion (Iadecola, 1998).

After long durations of ischemia, post-ischemic hyper-

emia is gradually offset by post-ischemic recirculation

disturbances (no-reflow phenomenon). If a severe

degree of focal ischemia persists for more than 2 h,

hemodynamic and functional restitution are severely

impaired and the resulting tissue injury approaches

that of permanent ischemia.

4.2.1. No-reflow phenomenon

The no-reflow phenomenon has been attributed to

several mechanisms: increased blood viscosity, increa-

sed coagulation, microvascular occlusion, increased

intracranial pressure, endothelial swelling, and post-

ischemic hypotension (Hossmann, 1997). It was ori-

ginally described by Ames et al. (1968) following

global cerebrocirculatory arrest. Small circumscribed

foci of no-reflow appeared after 7.5 min of ischemia

and affected the larger part of the brain volume when

ischemia was prolonged to 15 min. The concept of

the no-reflow phenomenon was extended by Crowell

and Olsson (1972) to transient focal ischemia. These

authors noted impaired microcirculatory filling after

temporary occlusion of the middle cerebral artery in

monkeys and concluded that these disturbances con-

tributed to the irreversibility of the lesion. No-reflow

was also described by Ito et al (1980) following caro-

tid artery occlusion in gerbils, which could, however,

be reversed by induced hypertension. It should be

noted that at normal blood pressure such disturbances

were observed only after several hours of ischemia,

i.e. after ischemia sufficient to cause irreversible

neuronal damage even in the absence of recirculation

disturbances. After focal ischemia of 1 h, which is tol-

erated without primary injury, blood flow returned to

normal within 5 min (Levy et al., 1979). It can, there-

fore, be disputed if no-reflow after transient focal

ischemia at normal blood pressure is of pathogenic

significance for infarct development or merely an

accompaniment to irreversible tissue injury.

4.3. Collateral circulation

The brain is well protected against focal interruption

of its blood supply by a number of extra- and intracra-

nial collateral systems (Fig. 4.2) (Hossmann, 1993).

The principal anastomoses connecting the main sup-

plying territories are located (1) between the two com-

mon carotid arteries; (2) between the external carotid

artery and the vertebral artery; (3) between the exter-

nal carotid artery and the intracranial circulation

through anastomoses with the ophthalmic artery; (4)

through the intracranial system of the circle of Willis

at the base of the brain; (5) across the leptomeningeal

anastomoses of Heubner; (6) through the arterial ring

anastomoses of Schmidt; and (7) through the capillary

anastomoses of Pfeifer.

The rich anastomotic connections between the caro-

tid and vertebral arteries provide a powerful collateral

system that is able to compensate for occlusion of up

to three of these arteries. The intracerebral collateral

circulation is much less efficient and depends almost

entirely on Heubner’s network of pial anastomoses on

the surface of the brain. The arterial ring anastomoses

of Schmidt are of importance for maintenance of some

collateral flow during thromboangiitis obliterans, and

the capillary anastomoses of Pfeifer for maintenance

of collateral flow following microembolization, but

neither of these systems is able to compensate for

ischemic blockade of a major intracerebral artery. It is

also important to note that the medial penetrating

arteries supplying the basal ganglia and brainstem are

not connected to other vascular territories and behave

functionally like end-arteries.

Owing to the pial arterial network, occlusion of a

major intracerebral artery usually results in infarction

of the central part and not of the total supplying terri-

ACAs

MCAsInternalcarotid art.

Internalcarotid art.

Internalcarotid art.

Basilary art.(A)

(B)

PCA PCA

MCA

MCA

ACA

ACA

PCA

PCA

Fig. 4.2. Collateral circulation of the brain. (A) The circle of Willis provides low resistance connections between the origins of

the anterior (ACA), middle (MCA) and posterior cerebral arteries (PCA). Reduction of blood supply by extracranial vascular

obstruction lowers blood perfusion pressure mostly in the peripheral branches of the brain arteries, leading to focal ischemia in

the border zones between the supplying territories (‘last meadow’ phenomenon). (B) Heubner’s leptomeningeal anastomoses

connect the peripheral branches of the brain arteries and provide collateral blood flow to the peripheral parts of the adjacent

vascular territories. Reduction of blood supply by intracranial occlusion of a brain artery lowers perfusion pressure mostly

in the proximal branches, leading to focal ischemia in the center of the vascular territory. (Modified from Zulch, 1985.)


tory. The actual size of the infarct is quite variable and

depends mainly on the number and vascular tone of

the leptomeningeal collateral channels, blood viscos-

ity, and blood perfusion pressure, which in turn is a

function of systemic blood pressure and intracranial

pressure. Computer simulations by Hudetz et al

(1982) revealed that middle cerebral artery occlusion

results in an infarct that covers about 50% of the terri-

tory of the middle cerebral artery when pial artery dia-

meter is 80 mm whereas dilation of pial arteries to

170 mm was able to completely prevent ischemia even

in the particularly endangered lenticulostriate areas.

This is the reason that young rats with a high capacity

for leptomeningeal vasodilation do not develop

infarcts after middle cerebral artery occlusion (Coyle,

1982), whereas in adult hypertensive rats, in which

the lumen of leptomenigeal vessels has narrowed,

infarcts may cover the whole supplying territory of

this artery (Coyle and Jokelainen, 1983).

The topography of ischemic lesions follows a differ-

ent pattern if cerebral blood flow is globally reduced,

e.g., by severe systemic hypotension or by multifocal

narrowing of the extracerebral supplying arteries in

advanced stages of atherosclerosis. Under these condi-

tions, blood flow is compromised initially in the periph-

ery and not in the center of the arterial territories

because the global reduction in blood perfusion pressure

results in the critical impairment of flow first in those

areas that are most distant from the arterial inflow. Since

these regions represent the borderlines between the sup-

plying territories of themain cerebral arteries, the result-

ing lesions have been termed ‘borderzone’ or watershed

infarcts. The hemodynamic situation leading to this type

of circulation failure has also been referred to as the ‘law

of the last meadow’ (Gesetz der letzten Wiese), in ana-

logy with the pattern of irrigation failure in agriculture

(Opitz and Schneider, 1950). The localization of such

infarcts on the brain surface is along the boundaries

between the territories of the anterior and middle and

the middle and posterior cerebral arteries, respectively,

and in basal ganglia in the terminal area of the lenticu-

lostriate arteries.

D

The dynamics of collateral blood supply after acute

vascular occlusion have been studied by vital micro-

scopy and angiography. At normotension, the collat-

eral leptomeningeal circulation functions within 30

seconds (Meyer and Denny-Brown, 1957). Within a

few minutes, a further dilation of the collaterals occurs

due to accumulation of metabolic waste products.

After collateral flow has been established, the

occluded middle cerebral artery is retrogradely filled

from both the anterior and posterior cerebral arteries.

Finally, within a few weeks after vascular occlusion,

collaterals may undergo arteriogenesis, i.e. the active

remodeling of preformed vessels, leading to enlarge-

ment of the circle of Willis (Busch et al., 2003) and

appearance of serpentine leptomeningeal vessels with

distinctly larger lumen than the pre-existing anasto-

moses (Coyle, 1982). As the vascular conductance

increases to the fourth power of the vessel diameter

(see below), collateral blood supply increases accord-

ingly. This explains why, once collateral circulation

has been established, it is not likely to fail secondarily

(Sundt and Waltz, 1971).

4.4. Hemorheology and microcirculation

According to the equation of Hagen and Poiseuille,

Newtonian flow through tubes equals

Q ¼ DPr4

�8l;

where Q is the flow rate, DP is the pressure gradient, ris the tube radius, l is the length of the tube, and � is

the viscosity of the fluid. This equation is frequently

given to describe blood flow through the vascular sys-

tem; however, it provides only a rough approximation

of the actual situation. Blood is not a Newtonian fluid

and blood viscosity changes as a function of hemato-

crit, erythrocyte deformability, flow velocity (or shear

rate), and the diameter of the blood vessels.

In the macrocirculation, i.e. in vessels larger than

100 mm, blood viscosity is mainly a function of

hematocrit and shear rate: it increases in a non-linear

way with decreasing shear rate (Schmid-Schonbein,

1981) and increasing hematocrit (Grotta et al.,

1982). The influence of hematocrit on viscosity is

most pronounced at a low shear rate, representative

of low flow. This is partly because of erythrocyte

aggregation, which increases with low and decreases

with high shear rate. With laminar flow, aggregates

form mainly in the central low-shear-rate part of the

vessels but they disaggregate again when they move

into the high-shear region along the vessel wall.

Aggregation is also influenced by alterations of coa-

gulation parameters and by surface characteristics of

CEREBRAL BLOOD FLOW AN

erythrocytes that, in turn, depend on membrane struc-

ture, electrostatic forces, the presence of macromole-

cules such as fibrinogen, serum osmolality, and

blood pH. All these factors change during ischemia

and have a tendency to facilitate erythrocyte aggre-

gation (Wood and Kee, 1985). Platelet aggregation,

in contrast to erythrocyte aggregation, is irreversible.

Aggregates formed in the center of the axial stream

do not disaggregate when moving to the outer lamina

but rather are exposed to additional mechanical

injury by the higher peripheral shear, causing a

further increase of their adhesiveness and aggrega-

tion (Wood and Kee, 1985).

In the microcirculation, the influence of hemorheol-

ogy and blood flow is even more complex. The cere-

bral microcirculation, by definition, is the vascular

bed distal to the penetration of arterioles 30–70 mmin diameter into brain parenchyma. At this dimension,

blood viscosity substantially changes with blood vessel

diameter. As was first described by Fahreus and

Lindqvist (1931), apparent blood viscosity initially

falls as vessel diameter decreases (Fahreus and Lindq-

vist effect) but, when vessel diameter is reduced to less

than 5–7 mm, viscosity again increases (inversion phe-

nomenon; Dintenfass, 1967). The critical radius below

which inversion occurs increases with increasing

hematocrit, increasing erythrocyte stiffness, increasing

erythrocyte or platelet aggregation, and decreasing

flow rate (Gaethgens et al., 1978). Accumulation of

polymorphonuclear leukocytes has been reported in

areas of low or heterogeneous blood flow (Hallenbeck

et al., 1986), resembling in pattern that noted for plate-

let accumulation (Obrenovitch and Hallenbeck, 1985).

Since these processes increase blood viscosity at the

microcirculatory level, blood flow is further reduced

and a vicious circle is initiated that enforces the pri-

mary ischemic impact.

Other studies, however, suggest that microcircula-

tory disturbances are a secondary phenomenon, with

the primary lesion being neuronal damage. In fact,

Little et al. (1975) noted only mild microvascular

obstruction following middle cerebral artery occlu-

sion for up to 3 h, whereas severe changes were pre-

sent after 6 h of ischemia. Detailed neuropathological

studies revealed that morphological alterations con-

sistently precede microcirculatory obstruction, indi-

cating that the observed disturbances were not the

critical factor for the evolution of the ischemic

infarction.

4.5. Regulation of cerebral blood flow

Because of the rigid nature of the skull and incompres-

sibility of the brain, it had long been thought that

THE ISCHEMIC PENUMBRA 71

ND

expansion of the cranial contents was severely limited

and that active changes in cerebral vessel caliber were

unlikely (Monro, 1783). This concept was later con-

firmed (Kellie, 1824) and became known as the

Monro–Kellie doctrine. It was not until 1890 that

Roy and Sherrington (1890) elucidated the two most

important concepts concerning the regulation of the

cerebral circulation: (1) that the brain has an intrinsic

mechanism to control its blood supply in accordance

with cerebral activity and (2) that chemical byproducts

of cerebral metabolism can lead to alterations in the

caliber of cerebral blood vessels.

4.5.1. CO2 reactivity

In intact brain, cerebral blood flow is tightly coupled

to the metabolic requirements of tissue (metabolic reg-

ulation) but remains constant in the presence of altera-

tions in blood pressure (autoregulation). Metabolic

regulation is reflected by the CO2 reactivity of cere-

bral vessels, which can be tested by the application

of carbonic anhydrase inhibitors or CO2 ventilation.

The effect of CO2 on the cerebral vasculature is pro-

nounced, easily demonstrated, and easily reproduced.

Cerebral vascular vasodilation and vasoconstriction

to increased and decreased CO2 are findings in mam-

mals at all ages. Under physiological conditions, blood

flow approximately doubles when CO2 is raised by

30 mmHg (Harper and Glass, 1965) and is reduced

by approximately 35% when CO2 is reduced to

25 mmHg (Reivich, 1964). The major factor account-

ing for the cerebrovascular response to CO2 is the

[H] of extracellular fluid but this mechanism could

work in conjunction with other influences such as

prostanoids or nitric oxide metabolism.

4.5.2. O2 reactivity

The effect of O2 on the cerebral circulation is also a

pronounced, easily demonstrated and reproducible

phenomenon. The brain has a high rate of aerobic

metabolism and thus depends on a continuous supply

of O2. Cerebral vasodilation and increased cerebral

blood flow are observed in response to oxygen chal-

lenges, including hypoxic hypoxia, carbon monoxide

hypoxia, and anemia hypoxia, and it is probably the

reduction in arterial O2 content rather than the O2 ten-

sion that is responsible for the increase of blood flow

(Traystman et al., 1978). A threshold for hypoxic

vasodilation exists at PO2 around 50 mmHg, below

which blood flow increases markedly (McDowall,

1966). Hyperoxia with 100% O2 breathing results in

mild cerebral vasoconstriction (Lambertsen et al.,

1953). Although it is clear that hypoxia produces cere-

72 K.-A. HOSSMANN A

bral vasodilation and a marked increase in cerebral

blood flow, the precise mechanism involved is unclear.

Hypotheses to explain this mechanism include direct

effects of O2, chemical or metabolic factors, and neu-

rogenic factors.

4.5.3. Autoregulation

The cerebral vasculature exhibits a remarkable capa-

city for autoregulation of cerebral blood flow; that is,

the relative constancy of cerebral blood flow over a

wide range of cerebral perfusion pressures (80–

150 mmHg) (Harper, 1966). This constancy in blood

flow is due to the active vasoconstrictions and vasodi-

lations occurring in response to increases and

decreases in pressure, respectively. The range of auto-

regulation may be shifted to the right with hyperten-

sion (Strandgaard et al., 1973) and to the left with

hypercarbia (Harper and Glass, 1965). Several the-

ories, which include myogenic, metabolic, and neuro-

genic influences, have been proposed to account for

the mechanism of autoregulation. The myogenic the-

ory proposes that changes in vessel diameter are

mediated by a direct effect of variations of blood pres-

sure on the myogenic tone of vessel walls. The meta-

bolic theory argues that some metabolic factor such

as CO2 or adenosine is the regulating factor. The neu-

rogenic notion proposes that autoregulation is

mediated by the adventitial nerves located on cerebral

vessels, but these may be secondary and not of great

significance.

4.5.4. Disturbances of flow regulation

During focal cerebral ischemia, tissue acidosis devel-

ops, leading to vasorelaxation and a severe disturbance

of the regulation of blood flow to autoregulation and

CO2 (Fig. 4.3). In the center of the ischemic territory,

CO2 reactivity is abolished or even reversed, i.e.

blood flow may decrease with increasing arterial

Pco2 (Symon, 1970; Waltz, 1970). This paradoxical

‘steal’ effect was attributed to the increase of blood

flow in non-ischemic adjacent brain areas that did

not lose CO2 reactivity (Hoedt-Rasmussen et al.,

1967) but this mechanism is disputed (Gogolak et al.,

1985), as described in more detail below.

Autoregulation is also disturbed following stroke

(Waltz, 1968; Symon et al., 1976), but the alterations

in blood flow are more severe with decreasing than

with increasing blood pressure. This is explained

by the fact that within the ischemic territory, local

cerebral perfusion pressure is below the lower limit

of autoregulation. A decrease in systemic blood pres-

sure cannot be compensated by further reduction of

R.J. TRAYSTMAN

λ + 1

0x

λ + 1

0x

λ + 1

0x

λ + 1

0x

17

16

15

14

13

12

11

10

19

18

17

16

15

14

13

12

19

18

17

16

15

14

13

12

17

16

15

14

13

12

11

10

60 90 120Arterial blood pressure Arterial blood pressure

CO2 reactivity

Regulation of blood flow

Autoregulation

Control

Control

MCA occlusion

MCA occlusion

150 180 mmHg 60 90 120 150 180 mmHg

0 20 40

Arterial pCO2

60 80 Torr 0 20 40

Arterial pCO2

60 80 Torr

Fig. 4.3. Regulation of blood flow in the territory of the middle cerebral artery of cat. Autoregulation was tested by pharma-

cological alterations of systemic blood pressure, and CO2 reactivity by ventilation with 6% CO2. After middle cerebral artery

occlusion both autoregulation and CO2 reactivity are abolished. l, unit of thermoclearance for measurement of blood flow.

(Data from Shima et al., 1983.)


vascular resistance; an increase in blood pressure,

however, may shift local perfusion pressure into the

autoregulatory range and cause vasoconstriction. This

is of particular importance for collateral vessels, which

originate in the non-ischemic tissue and therefore pre-

serve their vascular reactivity (Shima et al., 1983). An

alternative explanation for the preserved blood flow

response to increased blood pressure is ‘false autore-

gulation’ (Miller et al., 1975). In the presence of

edema, an increase in blood pressure is associated with

an increase in local tissue pressure, thus precluding a

substantial improvement of actual tissue perfusion

pressure. Failure of cerebral autoregulation can be

demonstrated in such instances by dehydrating the

brain in order to reduce brain edema.

After transient ischemia, vasorelaxation persists

for some time, which explains the phenomenon of

post-ischemic hyperemia or luxury perfusion. During

luxury perfusion, oxygen supply exceeds the oxygen

requirements of the tissue, leading to the appearance

of red venous blood. With the cessation of tissue

acidosis, vascular tone returns and blood flow declines

to or below normal. Subsequently, autoregulation, but

not CO2 reactivity, may recover, resulting in uncou-

pling of metabolic regulation. This may be one of

the reasons why primary post-ischemic recovery may

be followed by delayed post-ischemic hypoxia and

secondary metabolic failure (Hata et al., 2000b).

4.6. Segmental vascular response

Two types of brain vessel must be distinguished: the

superficial or conducting vessels and the nutrient

or penetrating vessels (Gillian, 1971). Conducting ves-

sels comprise the extracerebral segment of the vascular

bed and include the carotid and basilar arteries, the

ND

anterior, middle and posterior cerebral arteries, and the

network of interlacing branches of these arteries on the

surface of the brain (Heubner’s leptomeningeal anasto-

moses). Penetrating vessels and the associated capillary

network comprise the intracerebral segment of the brain

circulation. By recording the blood pressure difference

between the carotid and pial arteries on one hand, and

between the pial arteries and cerebrovenous outflow on

the other, segmental vascular resistances of the extracer-

ebral conducting and intracerebral nutrient vessels can be

calculated according to Ohm’s law (Shapiro et al., 1971;

Shima et al., 1983). In laboratory animals, about 50% of

total cerebral vascular resistance is accounted for by

extracerebral supplying vessels and 50% by intracerebral

nutrient vessels (Fig. 4.4) (Shapiro et al., 1971; Shima

et al., 1983). Both segments contribute equally to the

autoregulatory adjustment of vascular resistance; how-

ever, CO2 reactivity is controlled by the intracerebral

segment alone (Shima et al., 1983). This is in agreement

with the concept that CO2 reactivity reflects the behavior

of intracerebral (nutrient) vessels to alterations of

parenchymal metabolic activity, whereas autoregulation

74 K.-A. HOSSMANN A

Cortical blood flow

Arb

itrar

y un

its

161514131211109

100

80

60

40

20

0

% c

ontr

ol

0 20 40 60 80

mm HgPial artery pressure

EEG activity

0 20 40 60 80mm HgPial artery pressure

Fig. 4.4. Relationship between pial artery blood pressure measu

blood flow, segmental vascular resistance, the intensity of the enc

cular resistance is differentiated into an upstream segment, comp

segment that includes the intracerebral nutritional vessels. Pial a

middle cerebral artery. (Data from Date et al., 1984.)

is a myogenic response of the whole vascular system to

alterations of intraluminal pressure.

During middle cerebral artery constriction, resis-

tance of extracerebral supplying vessels rises and pial

arterial pressure falls (Date et al., 1984). Initially, this

decrease in pressure is compensated by an autoregulatory

dilation of the intracerebral vascular segment. As soon as

pial arteriolar pressure decreases to below 30 mmHg,

blood flow begins to fall and electrophysiological distur-

bances evolve (Fig. 4.4). At this level, the intracerebral

vascular segment is not yet fully dilated and vascular

resistance continues to decrease with further reduction

in blood flow (Date et al., 1984). This observation

demonstrates that acidosis, which develops during cere-

bral ischemia, causes a more pronounced vasodilation

than that induced by autoregulation alone.

After complete middle cerebral artery occlusion,

pial arterial pressure may be as low as 10–15 mmHg

(Shima et al., 1983; Date et al., 1984), and the back

pressure in the stump of the occluded artery is

less than 25% of the systemic pressure (Tulleken and

Abraham, 1975). If vascular occlusion is reversed, pial

R.J. TRAYSTMAN

Vascular resistance

Supplying arteries

Δm V

0−1−2−3−4−5−6−7

Arb

itrar

y un

its

12

10

8

6

4

2

0

Cortical steady potential

0 20 40 60 80

mm HgPial artery pressure

0 20 40 60 80mm HgPial artery pressure

red in the territory of cat middle cerebral artery and cortical

ephalogram and the cortical steady potential. Segmental vas-

rising the extracerebral supplying vessels, and a downstream

rtery pressure was lowered by transorbital constriction of the

D

arterial pressure increases and frequently even rises

above control level. The slope of this increase deter-

mines the quality of reperfusion and explains why

reversal of mechanical vascular occlusion results in

faster and more homogenous reperfusion and meta-

bolic recovery than thrombolytic recanalization, in

which reperfusion is more slowly restored (Hossmann,

1998).

4.7. Anastomotic steal phenomenon

The interconnection of ischemic and non-ischemic

vascular territories by anastomotic channels may

divert blood from one brain region to another, depend-

ing on the magnitude and direction of the blood pres-

sure gradient across the anastomotic connections. The

associated change of regional blood flow is called

‘steal’ if it results in a decrease in flow and ‘inverse

steal’ if it results in an improvement in flow. Inverse

steal has also been referred to as the Robin Hood syn-

drome (Lassen and Palvolgyi, 1968) by analogy with

the legendary hero who stole from the rich and gave

to the poor. Steals may be symptomatic or asympto-

matic, depending on the magnitude of the flow

changes. It has been suggested that the term ‘steal syn-

drome’ should only be used in the presence of neurolo-

gical symptoms, whereas in the absence of such

symptoms the terms ‘steal phenomenon’ or ‘steal

effect’ would be more appropriate (Von Vollmar,

1971).

Steals are not limited to a particular vascular terri-

tory and may affect both the extra- and intracerebral

circulation (for review see Toole and McGraw, 1975).

Examples of extracerebral steals are the subclavian,

occipital-vertebral and ophthalmic steal syndromes.

Intracerebral steals occur across collateral pathways

of brain, notably the circle of Willis and Heubner’s net-

work of pial anastomoses (see section 4.3, above). The

pathophysiological importance of steal phenomena for

the evolution of brain infarction has been vividly dis-

puted and still remains controversial. Evidence in favor

of intracerebral steal was provided in patients and ani-

mal experiments following ventilation with carbon

dioxide or anesthesia with halothane (Symon, 1968;

Waltz, 1970). The effect was explained by vasodilation

in non-ischemic brain regions, causing a decrease in

local cerebral perfusion pressure and, hence, a reduc-

tion of collateral blood supply to the ischemic territory.

Conversely, an inverse steal was noted during hyperven-

tilation, barbiturate treatment, and occlusion of the exter-

nal carotid artery (Lassen and Palvolgyi, 1968; Abraham

et al., 1971; Branston et al., 1979). The improvement

was related to vasoconstriction in intact brain regions

or—indirectly—to a decrease in intracranial pressure


causing improvement in cerebral blood perfusion pres-

sure. These findings, however, are at variance with other

observations that did not reveal alterations of blood flow

during either hypo- or hypercapnia (Meyer et al., 1972;

Harrington and DiChiro, 1973; Hanson et al., 1975).

Kogure et al. (1969) and Yamamoto et al. (1971) even

described improvement of blood flow and reduction in

size of the ischemic territory during ventilation with car-

bon dioxide. Steal—if it exists at all—seems to depend

on the individual hemodynamic situation and may lead

to unintended effects when flow in non-ischemic terri-

tories is manipulated. Most authors, therefore, do not

recommend such manipulations for the treatment of

stroke.

4.8. The penumbra concept of ischemia

The intact mammalian brain covers its energy needs

almost exclusively by oxidation of glucose. Opitz

and Schneider (1950) were the first to draw attention

to the fact that an impairment of energy production

induced by a reduction in oxygen supply affects the

energy-consuming processes in a sequential way: first

the functional activity of the brain is impaired, fol-

lowed, at a more severe degree of hypoxia, by the sup-

pression of the metabolic activity required to maintain

its structural integrity. The concept of two different

thresholds of hypoxia for the preservation of func-

tional and structural integrity was later refined by

Symon et al. (1977), who used a model of focal ische-

mia to establish the respective rates of blood flow.

These studies revealed that the EEG and evoked

potentials are disturbed at substantially higher flow

rates than the potassium gradient across the plasma

membranes (Fig. 4.5). Since the preservation of this

gradient is a sign of cell viability, Symon and his col-

leagues postulated that neurons located in the flow

range between ‘electrical’ and ‘membrane’ failure are

functionally silent but structurally intact. In focal

ischemia, this flow range corresponds to a crescent-

shaped region intercalated between the necrotic tissue

and the normal brain; it has been termed ‘penumbra’

by analogy with the partly illuminated area around

the complete shadow of the moon at full eclipse

(Astrup et al., 1981).

The penumbra concept of focal ischemia has been

partly revised over the years (Back, 1998; Sharp

et al., 2000; Touzani et al., 2001) but it remains of cru-

cial importance for the understanding of stroke patho-

physiology because it is the conceptual basis not only

for the progressive evolution of ischemic injury but

also for therapeutic reversal of the acute neurological

symptomatology arising from stroke (for reviews see

Hossmann, 1994; Heiss, 2000; Ginsberg, 2003; Fisher,


60

70

50

40SEPEEG

Peri-infarctdepolarizations

Penumbra concept of cerebral ischemia

Penumbra

Infarct core

30

20

10

0%

Cerebral blood flow

Proteinsynthesis

hsp72expression

Glucoseutilization

Lactacidosis

ATPdepletion

Anoxicdepolarization

PE

NU

M

BRA

Fig. 4.5. Thresholds of metabolic and electrophysiological disturbances during graded reduction of cortical blood flow. The

infarct core is the region in which blood flow decreases below the threshold of energy failure, and the penumbra is the region

of reduced blood flow in which energy state is preserved. EEG, electroencephalogram; SEP, somatically evoked potentials.

(Modified from Symon et al., 1977 and Hossmann, 1994.)


2004; Guadagno et al., 2004). Hakim (1987) defined

penumbra as ‘fundamentally reversible’ ischemic injury

but stressed that this reversibility is time-limited. Mem-

ezawa et al. (1992) described penumbra as the differ-

ence between the ischemic infarct developing after 1 h

and 24 h of vascular occlusion. Other characterizations

include the mismatch between magnetic resonance

(MR) perfusion and diffusion imaging (Schlaug et al.,

1999), the mismatch between suppressed protein and

energy metabolism (Mies et al., 1991), the expression

of stress proteins (Kokubo et al., 2003), the preservation

of oxygen extraction or receptor binding (Heiss, 2000),

intermediate staining with neutral red as an indicator

of beginning acidosis (Selman et al., 1987), or the loss

of calmodulin staining (DeGraba et al., 1993) as an indi-

cator of increased intracellular calcium uptake.

The common denominator of these and other defi-

nitions of the ischemic penumbra is the differentiation

between viable and non-viable tissue. Since viability

of brain tissue requires maintenance of energy-

dependent metabolic processes, we propose to define

penumbra as a region of reduced blood flow in which

energy metabolism is preserved (Hossmann, 1994).

4.9. Viability thresholds of ischemia

During the initial few hours of vascular occlusion, dif-

ferent brain functions break down at widely varying

flow levels (for references see Table 4.2). Progressing

from the periphery to the core of the infarct, the most

sensitive parameter is protein synthesis, which is

inhibited by 50% at about 0.55 ml/g/min and comple-

tely suppressed below 0.35 ml/g/min. These values

are clearly above the disturbances of glucose utiliza-

tion and energy metabolism, which begin to evolve

at distinctly lower flow values. Glucose utilization

transiently increases at a flow rate below 0.35 ml/g/

min before it sharply declines below 0.25 ml/g/min.

This range corresponds to the beginning of acidosis

and the beginning of accumulation of lactate. At flow

rates below 0.26 ml/g/min tissue acidosis becomes

very pronounced and phosphocreatine (PCr) and ade-

nosine triphosphate (ATP) begin to decline.

Anoxic depolarization occurs at even lower flow

values. The sodium/potassium ratio of brain tissue

increases at flow values below 0.10–0.15 ml/g/min

and extracellular ion changes occur between 0.06 and

0.15 ml/g/min. At the same threshold extracellular cal-

cium declines because of the opening of calcium chan-

nels. The metabolic and ionic disturbances in the

periphery of focal ischemia thus proceed in the follow-

ing order (Fig. 4.5): initially protein synthesis is inhib-

ited (at a threshold of about 0.55 ml/g/min), followed

by a stimulation of anaerobic glycolysis (below

0.35 ml/g/min), a breakdown of energy state (at about

0.20 ml/g/min), and anoxic depolarization of the cell

membranes (below 0.15 ml/g/min).

As far as functional disturbances are concerned,

the first change is the suppression of EEG activity,

which occurs below 0.25 ml/g/min. Evoked potentials

Table 4.2

Viability thresholds of ischemia

Threshold(ml/g/min

or % of control) Species Anesthesia Reference

Electrical activity

EEG 0.18–0.23 Gerbil Pentobarbital Naritomi et al., 1988

0.20 Macaca Awake Morawetz et al., 1979

0.15–0.20 Human Awake Sharbrough et al., 1973

Evoked potentials 0.15 Baboon a-chloralose Astrup et al., 1977


0.20–0.25 Cat Halothane Shimada et al., 1990

Unit activity 0.06–0.22* Cat Nitrous oxide Heiss and Rosner, 1983

Ion and water homoiostasis

Extracellular Kþ 0.06 Baboon a-chloralose Astrup et al., 1977


0.15 Rat Halothane Harris and Symon, 1984

Extracellular Ca2þ 0.06–0.09 Baboon a-chloralose Harris et al., 1981

0.15 Rat Halothane Harris and Symon, 1984

Na/K content 0.10–0.15 Cat Pentobarbital Hossmann and Schuier,

1980

Water content 0.10–0.15 Cat Pentobarbital Hossmann and Schuier,

1980

Extracellular space

Impedance 0.25–0.32 Cat Halothane Matsuoka and Hossmann,

1982

DWI 0.41 Rat Halothane Kohno et al., 1995

0.15–0.20 Gerbil Halothane Busza et al., 1992

Spreading depression

Increase duration 40% Rat Halothane Mies, 1997

Neurotransmitter release

Glutamate 0.20 Cat Halothane Shimada et al., 1989

0.20–0.30* Cat Halothane Matsumoto et al., 1993

48% Rat Halothane Takagi et al., 1993

Glycine 0.10–0.30 Cat Halothane Matsumoto et al., 1993

GABA 0.20–0.30 Cat Halothane Matsumoto et al., 1993

Adenosine 0.25 Cat Halothane Matsumoto et al., 1993

Metabolism

Protein synthesis < 0.80 Rat Halothane Jacewicz et al., 1986

0.55{ Rat Halothane Mies et al., 1991

0.49 Rat Halothane Kohno et al., 1994

> 0.40 Gerbil Halothane Xie et al., 1989

mRNA synthesis 0.25–0.30 Rat Halothane Kamiya et al., 2005

Glucose utilization

– Increase 0.35 Gerbil Halothane Paschen et al., 1992

0.20 Rat Halothane Yamamoto et al., 1988

– Decrease 0.25 Gerbil Halothane Paschen et al., 1992

Glucose 0.19–0.23* Rat Halothane Kohno et al., 1995

0.35 Gerbil Halothane Paschen et al., 1992

Lactate 0.30 Baboon a-chloralose Obrenovitch et al., 1988

Acidosis 0.25–0.30 Gerbil Halothane Allen et al., 1993

0.21–0.27 Gerbil Pentobarbital Naritomi et al., 1988

0.40–0.47* Rat Halothane Kohno et al., 1995

0.49 Rat Halothane Yamamoto et al., 1988

0.20–0.30 Baboon a-chloralose Obrenovitch et al., 1988

Phosphocreatine 0.20–0.25 Gerbil Halothane Allen et al., 1993

(Continued)


Table 4.2

(Continued)

0.18–0.23 Gerbil Pentobarbital Naritomi et al., 1988

0.20 Baboon a-chloralose Obrenovitch et al., 1988

ATP 0.12–0.14 Gerbil Pentobarbital Naritomi et al., 1988

0.20 Gerbil Halothane Paschen et al., 1992

0.13–0.19* Rat Halothane Kohno et al., 1995

0.19–0.32* Rat Halothane Mies et al., 1991

Inosine, hypoxanthine 0.25 Cat Halothane Matsumoto et al., 1992

Neurological disorder

Hemiparalysis 0.23 Macaca Awake Jones et al., 1981


Morphological changes

Neuronal loss < 0.80 Cat Pentobarbital Mies et al., 1983

Infarction

– Permanent ischemia 0.24 Rat Halothane Tamura et al., 1981

0.30 Rat Isoflurane Shen et al., 2003

0.17–0.18 Macaca Awake Jones et al., 1981

0.08 Human Awake Marchal et al., 1999

– Transient ischemia

1 hour < 20% Dog Thiopental Mizoi et al., 1987

2–3 h 0.10–0.12 Macaca Awake Jones et al., 1981


3–4 h 0.21–0.25 Rat Halothane Kaplan et al., 1991

DWI: diffusion weighted magnetic resonance imaging.

*Increase of threshold with time.

{No increase with time.


disappear between 0.15 and 0.25 ml/g/min and sponta-

neous unit activity at a mean value of 0.18 ml/100 g/

min. Neurological studies suggest that reversible hemi-

paralysis appears at about 0.23 ml/g/min, followed by

irreversible paralysis below 0.17–0.18 ml/g/min. All

these values are distinctly below the threshold of the

suppression of protein synthesis and even below that

of the beginning activation of anaerobic glycolysis but

they fall into the range of the beginning energy crisis.

This is also true for the release of neurotransmitters

into the extracellular compartment, as measured by

interstitial dialysis techniques. According to these

investigations, both inhibitory and excitatory neuro-

transmitters are released at about 0.20 ml/g/min, with

a possibly slightly higher threshold for glycine, adeno-

sine, and gamma-aminobutyric acid (GABA) than for

glutamate. The release of neurotransmitters is probably

unspecific because other intracellular metabolites are

co-released.

A direct consequence of the metabolic disturbances

associated with focal ischemia is the rise of cell osmol-

ality, which causes an osmotically driven shift of water

from the extra- into the intracellular compartment. The

resulting decline in the fluid volume of the extracellular

compartment can be detected bymeasurements of electri-

cal impedance or by diffusion-weighted imaging (DWI),

both of which are sensitive to cell volume changes. Some

2 h after vascular occlusion the threshold of the begin-

ning rise of electrical impedance is about 0.30 ml/g/min

and that of the rise of signal intensity in DWI is

0.41 ml/g/min. These thresholds are distinctly higher

than the threshold of brain edema—defined as the volu-

metric increase of water content—which is close to

0.10 ml/g/min and corresponds to that of anoxic depolar-

ization. This difference is probably the reason for the fact

that T2-weighted magnetic resonance imaging (MRI),

which detects alterations of tissue water content, is less

sensitive to mild ischemic changes than DWI.

In contrast to the biochemical and functional

changes, which appear shortly after vascular occlu-

sion, histological lesions require some time before

they become visible. The threshold of histological

changes, therefore, depends on both the density and

the duration of flow reduction. Under conditions of

permanent ischemia, the threshold of pan-necrosis is

between 0.17 and 0.24 ml/g/min. When ischemia is

D

reversed within 1–2 h, the tissue is able to survive a

reduction of flow to 0.12 ml/g/min. At flow values

below 0.80 ml/g/min, i.e. far above the threshold of

pan-necrosis, selective neuronal loss may occur. Inter-

estingly, this loss is not threshold-dependent: the flow

rate correlates linearly with the number of surviving

neurons, which suggests a coupled decrease in parallel

with the reduced metabolic requirements of the tissue.

This interpretation is in line with the hypothesis that

the peri-infarct brain tissue suffers pathological

changes that are not directly related to the reduction

of blood flow (see below).

Most of these thresholds have been determined at a

single time point a few hours following the vascular

occlusion. However, studies dealing with the

dynamics of infarct development clearly indicate that

the thresholds may change with time. In rats, the

threshold of ATP depletion increases from 0.13 ml/

g/min after 30 min to 0.19 ml/g/min after 2 h of vas-

cular occlusion and further to 0.23 and 0.32 ml/g/

min after 6 and 12 h respectively. Similarly, the

threshold of glutamate release rises from 0.20 ml/g/

min after 1 h to 0.30 ml/g/min after 6–15 h of ische-

mia. The threshold of the irreversible suppression of

spontaneous neuronal unit activity rises from 0.05 to

0.12 ml/g/min during the initial 2 h of vascular occlu-

sion, and that of the signal intensity in DWI—which

reflects alterations in the intra/extracellular water

compartmentation—from 0.41 to 0.47 ml/g/min

between 30 min and 2 h vascular occlusion. In con-

trast to these gradually progressing threshold values,

the threshold for the suppression of protein synthesis

remains remarkably stable at about 0.55 ml/g/min

during the initial 12 h of ischemia.

4.10. Imaging of the penumbra

Precise visualization of penumbra is of equal impor-

tance for the experimental elucidation of penumbral

pathophysiology as for clinical prognosis and treat-

ment decisions, such as thrombolytic treatment of

stroke (Kidwell et al., 2003). The penumbra can be

imaged either by quantitative mapping of hemody-

namic or metabolic alterations that conform to the

threshold definitions of penumbra (direct mapping) or

by delineating the mismatch between alterations that

affect only the core and others that affect both the core

and the penumbra (mismatch imaging). The reliability

of penumbral imaging depends not only on the defini-

tion of the penumbra but also on the rigor with which

the various penumbral markers have been validated

against independent methods. Other uncertainties of

penumbral imaging arise from the presence of multiple

penumbras for different molecular pathways (Sharp


et al., 2000), the absence or presence of post-ischemic

recirculation (Jansen et al., 1999), and the time-

dependent dynamics of penumbral viability (Hata

et al., 2000b). Finally, the differentiation between

penumbra and ‘benign’ oligemia that is not at risk of

infarction (Kidwell et al., 2003) is a problem of con-

siderable importance, particularly with regard to treat-

ment decisions. The selection of the appropriate

approach for penumbral imaging, therefore, requires

solid knowledge of the pathophysiological background

on which this approach is based.

4.10.1. Direct penumbral imaging

4.10.1.1. Cerebral blood flow

According to the threshold concept of cerebral ische-

mia, the penumbra can be delineated on quantitative

flow maps by drawing isocontour lines of flow values

that correspond to established thresholds of core and

penumbra (hemodynamic penumbra). Depending on

the definition of penumbra and the time of measure-

ment, flow values of 12–18 ml/100 g/min have been

reported to demarcate the penumbra from the core

region, and of 22–33 ml/100 g/min for the demarcation

between the penumbra and the surrounding intact tis-

sue (Heiss, 2000; Baron, 2001). The most reliable

method for experimental flow mapping is 131I- or14C-iodoantipyrin autoradiography, which provides

highly resolved flow data from cryostat sections of

brain (Fig. 4.1) (Sakurada et al., 1978). Non-invasive

quantitative flow measurements include, among

others, the 15O-H2O intravenous bolus method for

positron emission tomography (PET) scanning (Hers-

covitch et al., 1983), stable xenon computed tomogra-

phy (CT) (Meyer et al., 1981), MR perfusion imaging

using bolus tracking (Ostergaard et al., 1998) or arter-

ial spin labeling (Williams et al., 1992), and perfusion

CT with iodinated contrast material as an intravascular

tracer (Wintermark et al., 2001). Operationally defined

thresholds have also been derived from semi-

quantitative MR bolus track imaging with time-to-

peak values of 4–6 s for the transition between core

and penumbra (Grandin et al., 2002; Sobesky et al.,

2004). Similarly, prolongation of mean transit time or

time-to-peak of the impulse response (Tmax) by more

than 6 s demarcates tissue that progresses to infarction

(Parsons et al., 2001; Rohl et al., 2001). These num-

bers represent statistical values that vary in different

species and that change with duration of ischemia,

temperature, drugs, and the tissue compartment under

investigation. Precise demarcation of penumbra on

flow images, therefore, requires experimental or clini-

cal conditions in which the effects of these variables

are known and well controlled.


ND

4.10.1.2. Cerebral blood volume

The reduction of blood supply to brain evokes an autore-

gulatory dilation of resistance vessels that is reflected by

an increase in cerebral blood volume. However, as soon

as blood flow ceases, vessel tone exceeds intraluminal

pressure and cerebral blood volume declines. Penumbra

has, therefore, been associated with an increase of cere-

bral blood volume, as mapped by single-photon emission

CT (SPECT;Watanabe et al., 1999), perfusion CT (Win-

termark et al., 2001) or contrast-enhanced MRI (Oster-

gaard et al., 1998). Operationally, a blood volume

above 2.5 ml/100 g predicts tissue at risk (Wintermark

et al., 2002; Cheung et al., 2003) but the rather crude rela-

tionship between autoregulation and ischemic viability

thresholds precludes accurate delineation of penumbra

based on cerebral blood volume images.

80 K.-A. HOSSMANN A

4.10.1.3. Cerebral metabolic rate of oxygen

and oxygen extraction fraction

The quantitative mapping of cerebral metabolic rate of

oxygen (CMRO2) and oxygen extraction fraction by

PET is widely considered to be the gold standard of

penumbral imaging (Fig. 4.6) (Baron, 1999; Heiss,

Cerebral blood flow

12 hours

Flumazenil distribution Flumazenil

12 hou

12 hours 13 hou

Oxygen extract

Fig. 4.6. Transaxial positron-emission tomography mapping of c

zation, early flumazenil distribution, steady state flumazenil bind

acute onset of stroke. The contour delineating the MR-visible in

extraction fraction and reduced flumazenil binding. (Courtesy of

2000). Changes in oxygen extraction fraction can also

be visualized by near-infrared spectroscopy (Kurth

et al., 2002), MRI using multiecho gradient-echo/

spin-echo sequences (An and Lin, 2002), or the para-

magnetic blood-oxygen-level-dependent (BOLD)

effect (Turner et al., 1991; Crespigny et al., 1992).

As long as oxygen metabolism is preserved, a decline

in blood flow is associated with an increase in blood

oxygen extraction fraction. The increase in oxygen

extraction fraction is, therefore, thought to depict the

still viable penumbra, whereas cessation of CMRO2

is equivalent to cessation of metabolic activity in the

infarct core.

Correlation of oxygen extraction fraction maps with

final infarct size confirms the overall validity of this

approach (Heiss, 2003) but, from a conceptual point

of view, precise delineation of the core and penumbra

cannot be expected. In fact, oxygen extraction fraction

increases not only in the penumbra but also in areas of

‘benign’ oligemia, and CMRO2 ceases before energy

metabolism breaks down (see section 4.9, above).

The apparent borders of both core and penumbra are

therefore shifted outwards towards less severely

injured parts of the ischemic territory. In treatment

R.J. TRAYSTMAN

binding MR imaging

rs 14 days

rs 14 days

ion fraction Glucose utilisation

erebral blood flow, oxygen extraction fraction, glucose utili-

ing, and magnetic resonance (MR) imaging in a patient with

farct co-localizes precisely with the areas of reduced oxygen

W.-D. Heiss.)

D

studies this shift could lead to an overestimate of the

therapeutic effect because undamaged tissue that has

been misinterpreted as penumbra survives even with-

out any therapeutic intervention. However, as other

non-invasive mapping techniques present similar pro-

blems, oxygen extraction fraction and CMRO2 are

widely recommended as methods of choice for penum-

bral imaging.

4.10.1.4. Glucose utilization

With decreasing flow values and beginning tissue

hypoxia, glucose utilization transiently increases to

support anaerobic energy production before it preci-

pitously declines when blood glucose supply ceases

(Paschen et al., 1983; Yao et al., 1995). Glucose uti-

lization can be imaged invasively on histological

brain sections using the 14C-deoxyglucose method.

On such images the ischemic core is detected by

absence of and the penumbra by increase in glucose

utilization. With 18F-2-fluoro-2-deoxy-d-glucose

(FDG) as tracer, glucose metabolism can also be

imaged non-invasively by PET, albeit at lower reso-

lution. It has to be considered, however, that during

ischemia the lumped constant of the operational

equation—on which the calculation of glucose meta-

bolism is based—changes (Greenberg et al., 1992),

and that a steady-state condition for up to 45 min is

required for accurate measurement. Another problem

is the increase of glucose utilization during the pas-

sage of peri-infarct depolarization waves. As these

waves are not confined to the penumbra, they must

be excluded to avoid misinterpretation.


Blood flow

penumbra

penumbrahsp72 mRNA Protein

core

*

Tiss

Fig. 4.7. Imaging of infarct core and penumbra after middle cere

bolism (ATP) and protein synthesis are outlined and projected on

radiogram of hsp72 (below). Note correspondence of the biochem

of hsp72 upregulation. The area of ‘benign oligemia’ (*) does no

(Data from Mies et al., 1991 and Hata et al., 1998.)

4.10.1.5. Selective gene expression

With increasing use of high-throughput gene profiling

procedures for assessment of differential gene expres-

sion, a steadily increasing number of genes have been

associated with the evolution of penumbral injury

(Lipton, 1999; Read et al., 2001; Carmichael, 2003).

Pictorial evaluations of gene expression can be carried

out on histological sections at both the transcriptional

and translational level, using cDNA in situ hybridiza-

tion or immunohistochemistry respectively. Thus far,

the gene most closely associated with penumbra is

the cytosolic stress gene hsp-70, which is sharply upre-

gulated shortly after onset of ischemia and which is

thought to function as an endogenous protective

mechanism that facilitates renaturation of unfolded

proteins (Kinouchi et al., 1993). In fact, hsp-70 mRNA

expression co-localizes precisely with the mismatch

area between preserved energy and suppressed protein

synthesis that characterizes the biochemically defined

penumbra (Fig. 4.7) (Hata et al., 1998).

The low level of molecular oxygen in the penumbra

also results in upregulation of hypoxia-inducible factor

(HIF)-1 but this response expands more peripherally

into regions with ‘benign’ oligemia (Bergeron et al.,

1999). Genes indirectly linked to ischemia include the

immediate-early genes c-fos, c-jun and junB, whichare activated by peri-infarct depolarization waves (Kies-

sling and Gass, 1994). In accordance with the spread of

these waves, upregulation is not restricted to the penum-

bra but occurs throughout the ipsilateral hemisphere

(Hata et al., 1998). Finally, peri-infarct induction of a

large number of genes has been reported in association


synthesis

ue pH ATP

ATP

bral artery occlusion in rat. Areas of disturbed energy meta-

images of blood flow (above) and in situ hybridization auto-

ically characterized penumbra with hypoperfusion and area

t exhibit biochemical changes and is not at risk of infarction.

ND

with edema formation, inflammation, functional distur-

bances, and plasticity, albeit with poor spatial corre-

spondence to the penumbra and at greatly varying

delays after onset of stroke (Lu et al., 2004; MacManus

et al., 2004; Rickhag et al., 2006). They are, therefore, of

limited interest for penumbral mapping.

82 K.-A. HOSSMANN A

4.10.1.6. Tissue water properties

Ischemic injury is intimately associated with disturbed

water homeostasis, some properties of which can be

imaged for direct detection of penumbra. The most

important parameter is the apparent diffusion coeffi-

cient (ADC) of tissue water, which can be measured

by MRI and reflects the viscosity and tortuosity of

intra- and extracellular fluid spaces. At declining flow

values, stimulation of anaerobic glycolysis increases

intracellular osmolality and an osmotically driven

uptake of water, followed—at the threshold of anoxic

depolarization—by a massive shift of electrolytes and

water from the extra- into the intracellular compart-

ment. The resulting decline of ADC has been corre-

lated with blood flow and the associated biochemical

and structural changes of the tissue (Kohno et al.,

1995; Liu et al., 2003; Shen et al., 2004). Hoehn-Berlage

et al., (1995) reported in the rat middle cerebral

artery occlusion model that a decline of ADC to

90% of control correlates with the beginning of

acidosis and a further reduction to 77% with the

breakdown of energy metabolism. The ADC range

between these two values thus delineates the bio-

chemically defined penumbra. Other experimental

observations confirmed that a ‘mild’ decline from

850 to 800 mm2/s corresponds to penumbra whereas

a ‘large’ decline to 650 mm2/s (Miyabe et al., 1996)

or below 550 mm2/s (Kidwell et al., 2003) carries a

high likelihood of irreversible injury. With ongoing

ischemia time the cerebral blood flow threshold for

the ‘large’ reduction increases from 15 to 24 ml/

100 g/min (Kidwell et al., 2003). This is consistent

with the time-dependent increase in the threshold of

energy metabolism (Mies et al., 1991) and reflects

the gradual expansion of the infarct core into the

penumbra (see section 4.9, above).

An inherent problem of ADC mapping is the possi-

ble confusion of alterations caused by ischemia with

peri-infarct spreading depolarizations (Gyngell et al.,

1994). Unless such depolarizations are excluded by

appropriate electrophysiological monitoring, a reliable

differentiation between penumbra and intact tissue is

not possible. Finally, the possibility of a ‘pseudonor-

malization’ of ADC changes must be considered

(Warach et al., 1995). This phenomenon is caused by

accumulation of extracellular water due to vasogenic

brain edema and becomes of pathophysiological

relevance at about 1 week after stroke. However,

at this time, brain infarction is clearly detectable on

T2-weighted MRI, which allows the differentiation

from normal tissue.

Other tissuewater properties that have been associated

with ischemic brain injury and can be detected by MRI

are the increase in proton density and prolongation of

T1 and T2 relaxation times (Baird and Warach, 1998).

As these parameters reflect mainly the infarct core, they

can be used for mismatch imaging (see below) but are

of lesser interest for direct penumbral mapping.

4.10.1.7. Hypoxia marker

A clever approach for direct mapping of the ischemic

penumbra is the use of tracers that are trapped in

viable hypoxic but not in normoxic or necrotic tissue

(Chapman et al., 1983; Rasey et al., 1987). The best

characterized tracer of this kind is 18F-nitromidazol

(F-MISO) (Read et al., 1998; Saita et al., 2004). In

viable tissue F-MISO undergoes enzyme-mediated sin-

gle electron reduction of the nitro group to a free radical

anion. If tissue oxygen content is in the normal range,

the free radical anion is rapidly re-oxidized and cleared

from the tissue but under hypoxic conditions—as in

penumbra—re-oxidation is impaired and the compound

undergoes further reduction to reactive products that

bind to proteins and accumulate intracellularly. As the

first step of this process requires functional nitro-

reductase activity, it is blocked in the non-viable infarct

core. Nitroimidazoles are, therefore, true penumbral

markers that can be used for construction of ‘penum-

bragrams’ that map the spatial extension of penumbra

relative to the final infarct volume (Markus et al., 2004).

Hypoxia-dependent cell binding has also been shown

for iodoazomycin arabinoside (Lythgoe et al., 1997). In

rats with permanent middle cerebral artery occlusion

correlation with blood flow and DWI revealed

enhanced uptake of iodoazomycin arabinoside in

regions of reduced diffusion and perfusion (cerebral

blood flow threshold 34 � 7%) but not in the necrotic

infarct core or in oligemic tissue without disturbances

of water diffusion (Lythgoe et al., 1999). This is different

from the viability marker flumazenil, which binds to

viable tissue irrespective of diffusion properties and

which therefore does not allow differentiation between

penumbra and surrounding intact tissue (see below).

4.10.2. Mismatch imaging

The generation of mismatch maps is an extension of the

threshold concept of brain ischemia, which states that

the flow threshold for penumbral disturbances is higher

than that causing loss of tissue viability in the infarct core.

R.J. TRAYSTMAN

D

The mismatch of images reflecting these disturbances

corresponds to the peri-infarct penumbra. An important

methodological requirement for the generation of such

maps is the acquisition of two different images from the

same brain slice, performed either simultaneously or at

short interval. Various invasive and non-invasive meth-

ods have been proposed for this purpose.

4.10.2.1. ATP mismatches

Under animal experimental conditions the most obvious

biochemical marker of core injury is breakdown of

energy metabolism. Spatially highly resolved images of

tissue energy state are obtained by bioluminescencemap-

ping of the ATP content of cryostat sections prepared

from in situ frozen brains (Kogure and Alonso, 1978).

These images can be matched with maps of alterations

that evolve at higher flow thresholds and include both

core and penumbra (Fig. 4.7). Examples of these are auto-

radiographic images of reduced protein synthesis (Xie

et al., 1989), images of tissue acidosis obtained by fluoro-

scopic (Csiba et al., 1983), autoradiographic (Kobatake

et al., 1984), or histochemical approaches (Van der Veer

et al., 1985), fluoroscopic images of increased nicotina-

mide adenine dinucleotide (NADH) content (Welsh

et al., 1991) and bioluminescence images of increased

lactate (Paschen, 1985). As thresholds of these alterations

differ slightly, the corresponding mismatch maps

also vary, in accordance with the concept of multiple

penumbras (Sharp et al., 2000). Mismatch maps also

change with ongoing time after stroke onset because the

flow threshold for the breakdown of energy metabolism

gradually increases, reflecting expansion of the infarct

core into the peri-infarct penumbra (Mies et al., 1991).

This phenomenon has been best documented by imaging


ATP bioluminescence

Penumbra

1 hour 3 hours

Protein synthesis

core

Fig. 4.8. Time-dependent expansion of infarct core into penum

Simultaneous imaging of tissue content of ATP and protein synth

ischemia time. (Data from Hata et al., 2000a.)

ATP and cerebral protein synthesis after increasing dura-

tions of experimental middle cerebral artery occlusion

which reveals the gradual disappearance of ATP/cerebral

protein synthesis mismatch within 6–12 h (Hata et al.,

2000a) (Fig. 4.8).

As an alternative to ATP mapping, core tissue can

also be detected by vital stains such as triphenyltetra-

zolium chloride (Hatfield et al., 1991), high-contrast

silver infarct staining (Vogel et al., 1999), or histochem-

ical stainings of the total tissue content of calcium

(Araki et al., 1990) and potassium (Mies et al., 1984),

which change inversely after anoxic depolarization.

However, these alterations require some time for evolu-

tion and are not suited for acute mismatch mapping.

4.10.2.2. Diffusion/perfusion mismatch

A widely accepted although not rigorously validated

signature of irreversible brain injury is the increase in

signal intensity in DWI. The combination of such images

with blood perfusion-weightedMR images (PWI) has led

to the DWI/PWI mismatch concept, which states that the

penumbra is the area of reduced blood flow in which

alterations of water diffusion are absent (Fig. 4.9) (Soren-

sen et al., 1996; Neumann-Haefelin et al., 1999). This

assumption is not undisputed, however (Kidwell et al.,

2003). The apparent diffusion coefficient of tissue water

begins to change before energy metabolism fails, indi-

cating that DWI-detectable areas include parts of

the penumbra (Kohno et al., 1995). The PWI-detectable

area of reduced blood flow, in turn, is not based on

quantitative thresholds and varies with the MR method

used. Hypoperfusion, therefore, includes an undefined

volume of ‘benign’ oligemia in which blood flow is

reduced but still adequate to support metabolic needs of


6 hours 1 day 3 days

bra after permanent occlusion of the middle cerebral artery.

esis. Note gradual disappearance of penumbra with ongoing

Core

MCA occlusionControl

ADC

PWI

Penumbra

Core

Fig. 4.9. Magnetic resonance (MR) diffusion-perfusion mismatch for the demarcation of infarct core and penumbra after occlusion

of middle cerebral artery in rat. The mismatch area is highlighted by projecting the outline of the area of disturbed diffusion (as

detected on quantitative ADC maps) on the perfusion-weighted MR image (PWI) (courtesy of L. Olah and M. Hoehn).


the tissue (Parsons et al., 2001). Compared to quantitative

biochemical and hemodynamic maps of the penumbra,

DWI/PWI mismatch is, therefore, only an approximation

of the real situation, with a marked tendency for overesti-

mation of the size of the penumbra (Grandin et al., 2002;

Sobesky et al., 2004). The inclusion of ‘benign’ oligemic

tissue is reflected by the long persistence after stroke onset

of PWI/DWImismatch, which in 44% of stroke patients is

still detected at 18–24 h (Darby et al., 1999). This is much

longer than the experimentally determined survival time of

penumbra and, if misinterpreted as an indication for late

reperfusion therapy, could provoke hemorrhagic and other

complications. However, preliminary data from ongoing

stroke trials designed to confirm clinical utility of the

MR mismatch hypothesis indicate that the demarcation

of penumbra may not be critical because reperfusion ame-

liorates tissue fate irrespective of mismatch (Butcher et al.,

2005; Hacke et al., 2005).

4.10.2.3. Loss of receptor binding

Areliable non-invasive signature of tissue viability is bind-

ing of SPECT- and PET-detectable radioligands, 123I-

iomazenil or 11C-flumazenil, to the benzodiazepine site

of the neuronal GABA receptor (Sette et al., 1993; Al-

Tikriti et al., 1994). In focal ischemia early loss of recep-

tor binding predicts irreversible infarction with high

probability, under both experimental and clinical condi-

tions (Sette et al., 1993; Watanabe et al., 2000; Heiss

et al., 2004). The mismatch between absence of fluma-

zenil binding and areas of either reduced blood flow or

increased oxygen extraction fraction thus provides a

pathophysiologically well supported estimate of

ischemic penumbra (Fig. 4.6). In fact, comparison of

this approach with DWI/PWI mismatch maps revealed

a similar predictive power but a lower incidence of

false-positive results (Heiss et al., 2004), which is read-

ily explained by the more precise detection of the infarct

core using flumazenil (see above). However, as demar-

cation of brain regions with normal and reduced fluma-

zenil binding takes some time, flumazenil imaging is not

suited for fast treatment decisions, as required for the

early initiation of thrombolysis in acute stroke.

4.10.2.4. Other imaging modalities

In principle, any neuroimaging method with different

thresholds for core and penumbra can be combined to pro-

duce penumbral mismatch maps. Examples of such

combinations are MR spectroscopic imaging of N-acety-laspartate (which declines in core due to the loss of irre-

versibly injured neurons) and lactate (which increases

both in core and penumbra) (Barker et al., 1994), or ima-

ging of blood volume (which increases in penumbra due

to autoregulatory vasodilation) in combination with CT

scans or other anatomical images of the structurally

injured infarct core (Grandin et al., 2001; Lee et al., 2002).

An indicator of functional impairment that charac-

terizes the penumbra is the activation of voltage- and

receptor-operated calcium channels. These channels can

be detected in vivo by binding to nimodipine (Hakim

and Hogan, 1991) or dizocilpine (Di and Bullock,

1996). It has not been clearly established, however, if

increased binding co-localizes only with the penumbra

or also with the core of the evolving infarct.

4.10.3. Penumbral imaging during reperfusion

According to the concept of flow-dependent viability

thresholds, penumbral tissue escapes lasting damage

when blood flow is restored to normal levels before

structural changes have evolved (Symon et al., 1977).

D

In fact, prevention of brain infarction after restitution

of blood flow is an important argument for the opera-

tional definition of penumbra (Schlaug et al., 1999;

Shih et al., 2003; Butcher et al., 2005). However, as

the dynamics of post-ischemic reperfusion greatly

vary, tissue may remain at risk of infarction despite

successful recanalization. Obviously, hemodynamic

or flow-related penumbral markers are not suited for

detection of such areas but metabolic or tissue signa-

tures of penumbra, such as the mismatch between

ATP and cerebral protein synthesis, increased glucose

utilization, upregulation of stress genes, or reduced

ADC levels, provide valuable information on the per-

sistence or reversal of penumbral injury (Fig. 4.10)

(Hata et al., 2000b; Izaki et al., 2001; Kokubo et al.,

2003). Penumbral imaging is also of great interest for

predicting delayed ischemic injury. Depending on

ischemic duration and severity, reperfusion may

reverse part of the core injury, as reflected by restora-

tion of energy metabolism or reversal of ‘large’ ADC

reduction (Hata et al., 2000b; Fiehler et al., 2002) but

despite adequate blood circulation these regions

remain at risk of secondary infarction. During the

interval between primary metabolic recovery and sec-

ondary cell death these regions exhibit ATP/cerebral

protein synthesis mismatch, mild ADC decline and

hsp-70 upregulation, by analogy with the ‘true’

ischemic penumbra (Hata et al., 2000b; Olah et al.,

2000; Kokubo et al., 2002). This points to similar

injury mechanisms and suggests that neuroprotective

interventions may be equally effective during reperfu-

sion as during ischemia.


penumbra

core

release1 hour1 hour

Ischemia

ATP bioluminescence

Protein synthesis

Fig. 4.10. Reversal of focal ischemia after mechanical occlusion

tissue ATP content and protein synthesis. Note rapid restoration

not of protein synthesis. A few hours after restoration of blood flo

protein synthesis did not recover. (Data from Hata et al., 2000b.

4.10.4. Practical recommendations for penumbral

imaging

Important criteria for selection of the most appropriate

approach for penumbral imaging are the choice

between invasive or non-invasive methods on the one

hand and between direct and mismatch imaging on

the other. For animal experimental purposes, in which

brain tissue can be dissected at the end of experiment,

ATP/cerebral protein synthesis or ATP/pH mismatch

imaging provides spatially highly resolved penumbra

maps that are sharply demarcated from both the

ischemic core and the surrounding intact tissue,

including areas of ‘benign’ oligemia in which adequate

oxygen delivery is maintained (Mies et al., 1991; Hos-

smann, 1994). ATP/cerebral protein synthesis or ATP/

pH mismatch maps can be generated without prior

knowledge of the particular viability thresholds, as

required for quantitative blood flow or ADC maps,

and they identify tissue at risk both during ischemia

and reperfusion. Obviously, this approach is restricted

to animal experiments but if with improving sensitivity

of MR spectroscopy non-invasive phosphorus imaging

should become feasible, ATP mismatch maps could be

acquired in patients and would serve as reliable stan-

dards for validation of other penumbral imaging mod-

alities.

Under clinical conditions and for animal experiments

that require repeated measurements, the two methods of

choice are DWI/PWI mismatch imaging using MR

technology (Abe et al., 2003; Warach, 2003) and ima-

ging of blood flow, oxygen consumption, oxygen


3 hours 6 hours 3 days

Reperfusion

of the middle cerebral artery for 1 h. Simultaneous imaging of

of energy metabolism after release of vascular occlusion but

w, energy metabolism secondarily fails in the areas in which

)

ND R.J. TRAYSTMAN

extraction fraction, and flumazenil binding using PET

(Baron, 1999; Heiss, 2000). PET studies are quantita-

tive and therefore considered by many to be the gold

standard for penumbral imaging but they require expen-

sive instrumentation, prior knowledge of individual via-

bility thresholds (for quantitative cerebral blood flow

and CMRO2 maps), and the manifestation of structural

injury (for flumazenil maps) to allow precise demarca-

tion from the core and the surrounding intact tissue.

DWI/PWI mismatch imaging, in contrast, is readily per-

formed with most clinical MR scanners, does not

require prior knowledge of individual viability thresh-

olds, does not have to await structural manifestation of

injury, and provides excellent spatial resolution even

in small-animal brains. However, uncertainties about

the demarcation between penumbra and core on the

one hand and between penumbra and ‘benign’ oligemia

on the other preclude precise spatial allocations. Direct

comparisons of PET and MRI data in the same subject

demonstrated that the predictive power for the evolution

of brain infarction is similar for both methods (Heiss

et al., 2004) but, as MRI provides a less precise alloca-

tion of penumbra, PET is the preferred method for basic

pathophysiological studies. Neither, however, matches

the spatial resolution and pathophysiological unambigu-

ousness of invasive metabolic imaging techniques such

as ATP/cerebral protein synthesis mismatch mapping.

Validation of new penumbral mapping proced-

ures should, therefore, be based on this or similar

approaches.

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[Handbook of Clinical Neurology] Stroke Volume 92 || Chapter 4 Cerebral blood flow and the ischemic penumbra