REWIEW
Imaging the ischemic penumbra and treatment effects by PET
Wolf-Dieter Heiss
Max Planck Institute for Neurological Research and Department of Neurology, University of Cologne
Cologne, Germany(Received for publication on June 28, 2001)

Abstract. Active treatment of acute ischemic stroke can only be successful as long as tissue in the areaof ischemic compromise is still viable. Therefore, the identiﬁcation of the area of irreversible damage,and its distinction from the penumbral zone, i.e., tissue with impaired function but preserved morphology, may improve the estimation of the potential efﬁcacy of various therapeutic strategies. This canbe achieved by multi-tracer positron emission tomography (PET), perfusion-weighted and diffusionweighted magnetic resonance imaging in experimental models. Neuroimaging modalities applied inpatients with acute ischemic stroke cannot reliably identify penumbra tissue and detect irreversible
damage in the ﬁrst hours after stroke, when treatment must be initiated to have the potential for success: multitracer studies for the assessment of ﬂow and irreversible metabolic damage usually are limitedin the clinical setting, and arterial blood sampling necessary for quantitative determinations is prohibited
under certain circumstances, e.g., when thrombolysis is planned. The range of the penumbra can beassessed by combining determinations of ﬂow and benzodiazepine receptor binding by PET of H2 15 O
and 11 C-ﬂumazenil (FMZ) and relating ﬂow values and FMZ binding to the ﬁnal state of the tissue. By
this approach, cumulative probability curves can be computed to predict eventual infarction or noninfarction and to deﬁne the penumbral range. The computed values are in good agreement with resultsfrom other studies proving the validity of the concept of the penumbra which was also demonstrated inseveral therapeutic studies in which thrombolytic treatment reversed critical ischemia and decreased
the volume of the ﬁnal infarcts. Such neuroimaging ﬁndings might serve as surrogate targets in the selection of other therapeutic strategies for large clinical trials. (Keio J Med 50 (4): 249–256, December
2001)
Key words: ischemic stroke, irreversible damage, penumbra, therapeutic window, positron emission
tomography

Introduction
In the treatment of acute ischemic stroke two primarystrategies can be followed: limitation of the ischemic
insult by early reperfusion and interference with thepathobiochemical cascade leading to ischemic neuronaldamage. A necessary prerequisite for either strategy isthe existence of functionally impaired but viable andpotentially salvageable tissue; irreversibly damaged tissue should be excluded or limited in its extent, sincesuch tissue could not beneﬁt from any strategy andforced reperfusion could even be detrimental by causing hemorrhage and/or edema. Severity and extent of
the ischemic compromise can be clearly assessed in experimental models for which ﬂow thresholds for pres-ervation of function and morphology were deﬁned.1
Tissue perfused at a value between the thresholds forpreservation of morphological integrity and of function, i.e., penumbra tissue, might regain function withimprovement of ﬂow, but the time periods tolerated
depend on ﬂow levels and on severity of metabolic
disturbances. In consequence, therapeutic windows
are postulated for effective restoration of blood ﬂow
and for successful intervention with biochemical alterations,2 but the durations of these windows are dependent on the residual perfusion in the tissue and therefore are different for the core and the periphery of theischemic territory.
In the clinical setting of acute stroke management
the assessment of the condition of the ischemicallyReprint requests to: Dr. Wolf-Dieter Heiss, Professor, Max Planck Institute for Neurological Research and Department of Neurology, University of Cologne, Gleueler Strasse 50, D-50931, Cologne, Germany
249

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affected tissue is extremely difﬁcult and necessitateslogistically complex and expensive investigative procedures, which usually cannot be performed. However,such studies in selected cases have broadened theknowledge of pathophysiologic mechanisms leading toischemic infarction. The results of these investigations
additionally may help to explain the success or lack ofefﬁcacy of different therapeutic strategies.
Clinical Evidence for Viable Tissue as an Equivalent
to Ischemic Penumbra
The most pertinent results of pathophysiologicchanges during the early course after ischemic stroke
have been obtained by multitracer positron emission
tomography which provides quantitative maps of several important physiologic variables including regional
cerebral blood ﬂow (rCBF), regional blood volume, regional cerebral metabolic rate of oxygen (rCMRO 2 ),and regional cerebral metabolic rate of glucose(rCMR glc ) (Fig. 1). These studies conclude that tissue
with rCMRO 2 below 65 mmol/100 g/min and/or rCBF
below 12 ml/100 g/min over time turns into necrosis.3,4
Regions with rCBF between 12 and 22 ml/100 g/min
have unstable function, and they must be considered as
the penumbra zone, because infarction will occur in sucha region if those low-ﬂow values persist.5,6 Uncoupled

Heiss W-D: PET of ischemic penumbrachanges of ﬂow and metabolism indicate the existenceof viable but insufﬁciently supplied tissue in an ischemic
region: the early perfusion failure manifests itself as adecrease in rCBF with rCMRO 2 and rCMR glc remaining relatively preserved. This condition, called misery
perfusion,3 implies that blood ﬂow is inadequate relative to the metabolic energy demand for oxygen andsubstrate for still viable tissue (Fig. 1).
In repeat multitracer positron emission tomography
studies of acute ischemic stroke6–8 with differentiation
between the ischemic core and periphery by identiﬁed
and matched small regions of interest, it could be demonstrated that viable but misery perfused tissue exists inthe border zone of ischemia up to 17–48 hours after
stroke. Only in a few regions or in special cases with increased oxygen extraction fraction and slightly impaired
rCMRO 2 , was metabolism preserved close to normal
values, and tissue remained morphologically intact.
Most tissue compartments showing misery perfusion in
the ﬁrst day however suffer progressive metabolic derangement and turn into necrosis during the following
two weeks. Whereas the viable peri-infarct penumbra
tissue exhibits some potential for effective treatment,
therapeutic routine available today in most cases cannot prevent subsequent progression to necrosis.
Correlative PET Studies in Animal Models

Fig. 1 Upper trace: sequential PET images from an individual cat
representing CMRO 2 , CBF and OEF before (control) and at 2 time
points (1 and 20 h) after left MCAO. Progressive deterioration ofoxygen consumption in the MCA territory corresponds with the
spreading of the area with increased OEF and ﬁnally leads to hemodynamic and metabolic derangement, seen in the ﬁnal CMR glc image
and in the corresponding histological cross section showing the area of
infarction at the same time point. Lower trace: patient study demonstrating correspondence of regions exhibiting early (12 h) severe perfusional and metabolic deﬁcits and decreased OEF in the anterior
ischemic territory with ﬁnal (14 days) deﬁcit in CMR glc and infarction
observed by MRI and of regions showing a moderate perfusionaldeﬁcit and increased OEF in the posterior ischemic territory with
better preserved CMR glc and no infarction.

In the clinical setting, only a few of the many factors
contributing to the complex process of ischemic tissue
damage, like blood ﬂow, blood volume, oxygen consumption, and glucose metabolism can be assessed byfunctional imaging techniques. Additionally, the clinicalstudies are restricted to incidental time points in thecourse of the disease, and the complicated logistics involved in the regional determination of the physiologic
variables prevent their repeated evaluation early after
an ischemic attack, which is when the fate of the patientis decided. In order to better understand the resultsof multitracer PET studies in early stroke reproducible
animal experiments are necessary in which regionalchanges in physiologic variables can be followed fromthe vascular attack to the permanent defective state andthen be related to histologic alterations. With advanced
PET equipment it became feasible to study pathophysiologic changes in brain perfusion and metabolism
after MCA occlusion in baboons 9,10 and cats.11
In cats in whom CBF, CMRO 2 , OEF, and CMR glc
were followed from control values before ischemia tothe endpoint of infarction 24 h after MCAO, CBF
within the MCA territory fell immediately upon arterial
occlusion to below 30% of control, whereas CMRO 2 wasless diminished and consequently OEF was increased,thus indicating ‘‘misery perfusion’’. This ischemic penumbra spread with time from the center to the borders

Keio J Med 2001; 50 (4): 249–256

Fig. 2 Left side: sequential PET images from an individual cat undergoing 60-min MCAO and reperfusion resulting in a favorable outcome. Images represent CBF, CMRO 2 and OEF before (control),
immediately after and at the end of MCAO and after reperfusion.
During the ischemic episode, CMRO 2 did not deteriorate further and
OEF remained increased. Hyperperfusion was not pronounced in thisparticular cat, and ﬁnal CMR glc did not show major deﬁcits. Rightside: patient study demonstrating successful reperfusion after thrombolysis. Structural damage as determined by MRI did not occur in thisparticular case.

of the MCA territory. In most instances the misery perfusion condition was followed by a marked OEF drop
reﬂecting progressive impairment of blood ﬂow andmetabolism and suggesting transition to necrosis, andthe infarcts were more or less complete 18–24 h after
MCAO (Fig. 1). Occasionally, spontaneous collateralreperfusion resolves the penumbra condition and morphologic integrity of the cortex is preserved.
Reversible MCAO was studied in cats12 with reopening of the MCA after 60 min. Whereas in the animals surviving 24 hours of reperfusion OEF remained
elevated throughout the ischemic episode (Fig. 2), theinitial OEF increase disappeared already during 60 min
ischemia in those cats that died during the reperfusion
period (Fig. 3). In cats dying during the observation
period, extended postischemic hyperperfusion accompanied large defects of CMRO 2 and CMR glc , large infarcts developed and intracranial pressure increased
fatally. These results further stress the importance ofthe severity of ischemia in relation to its duration for
the further course after reperfusion. They also showthat the penumbra is a dynamic process. The time window for eventual recovery of tissue – important as thetherapeutic window – is therefore different for the coreof dense ischemia (where it is short, probably below 1 h
in the cat) and the vicinity with graded perfusional disturbance, where it is certainly several h and might251

Fig. 3 Left side: sequential PET images from an individual cat undergoing 60-min MCAO and reperfusion resulting in an unfavorable
outcome. Images represent CBF, CMRO 2 and OEF before (control),
immediately after and 30 min after MCAO and after reperfusion.
During the ischemic episode, CMRO 2 deteriorated further and theinitially increased OEF decreased already during ischemia. Afterreperfusion, pronounced hyperperfusion occurred in this particularcat, and ﬁnal CMR glc showed major deﬁcits. Right side: patient study
demonstrating only partially successful reperfusion after thrombolysis(frontal part of ischemic focus), resulting, however, in pronounced
hyperperfusion. Structural damage as determined by MRI occurred inthis particular case in both nonreperfused and hyperperfused portionsof the ischemic territory.

extend to 24 h in the cat or to several days in the monkey.13
PET studies in animal models simulate the course of
perfusional and metabolic disturbances characteristic
for ischemic stroke in humans: permanent MCAO
resembles the natural course after vascular occlusion
leading to large infarcts in most cases (Fig. 1), with achance of collateral reperfusion resolving misery perfusion and improving outcome. Reopening of the MCA
resembles the (spontaneous) dissolution of vascularocclusions in transient ischemic attacks, spontaneous
lysis of emboli after a period beyond the tolerable time
period, and therapeutic thrombolysis. During MCAO
of longer duration two patterns can be distinguished:decrease of the OEF during the time of MCAO reﬂects
fast irreversible damage of tissue (Fig. 3), whereas thepersistence of raised OEF indicates preserved viabilityof tissue over the ischemic period (Fig. 2). Forced reperfusion by reopening of the MCA cannot salvage already irreversibly damaged tissue, but may cause additional damage by inducing edema via leaking vascularendothelium as also observed with thrombolysis initiated too late.

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Heiss W-D: PET of ischemic penumbra

Flow Compartments within Final Infarcts
Reperfusion induced by thrombolysis has been shown
to be an effective therapeutic strategy in acute ischemic
stroke when initiated within 3 hours of onset of symptoms.14 In contrast, neuroprotective strategies thus far
have been disappointing clinically and were unsuccessful
with respect to improving stroke outcome15 althoughsigniﬁcant reductions of infarct size were demonstrated
in animal models with the use of strategies to antagonize
the various steps in the excitotoxic cascade,16 or free
radical toxicity,17 to inhibit harmful secondary inﬂammatory mechanisms18 or to attenuate cell death by
apoptosis.19 This discrepancy is in part due to the limitsof animal models concerning the complexity of clinicalstroke, but it is also attributed to differences in outcome
endpoints chosen for evaluation of therapeutic effects:
reductions of infarct size in a particular experimental
setting may in fact be poor predictions of functional
outcome of stroke patients, especially since the relative
impact of the various mechanisms contributing to theﬁnal infarct may be different in human stroke.
In order to determine various subcompartments
of infarcts with respect to severity of initial ischemia,
rCBF was assessed by H2 15 O and PET in 10 patientswith ischemic hemispheric stroke within 3 hours ofsymptoms onset. Within the boundaries of the ﬁnal
infarcts outlined on 3D-coregistered magnetic resonance images 2–3 weeks after the stroke, the following
compartments of gray matter were identiﬁed according
to their regional tracer uptake relative to the contralateral hemispheric mean,20 (a) below 50%, representing the critical threshold of 12 ml/100 g/min,3,4 (b)between 50 and 70%, representing the penumbra of 12–
18 ml/100 g/min,5 (c) above 70%, representing tissue
outside the territory with markedly impaired perfusion.
The ﬁnal gray matter infarcts varied considerably
in size (median 27.7, range 1.5–138.4 cm 3 ). All of thethree predeﬁned ranges of initial ﬂow were found ineach of the infarcts. However, despite large variability
among individuals, the largest proportion by far was the
sub-compartment of critical hypoperfusion (51–92% of
the ﬁnal infarct), followed by penumbral tissue (8–34%), whereas the subcompartment initially perfused
at a sufﬁcient level was relatively small (2–25%). Only
in one case, with a ﬁnal infarct of 15.6 ml, the subcompartment of sufﬁcient initial ﬂow was large (41%)
and the critically hypoperfused volume relative small(31%).
These data indicate that the ﬁnal infarcts werecaused mainly by severe initial ischemia leading to immediate tissue damage, while other mechanisms played
only a minor role. Since the subcompartment of theinfarct caused by delayed damage is too small to be a
promising target of therapy, the beneﬁt from treatment

directed against those post-primary mechanisms is necessarily limited – and the disappointing results of corresponding clinical trials are not surprising. The penumbral tissue, another rather small fraction of the ﬁnal
infarct, can proﬁt from reperfusion in due time, while
neuroprotective drugs alone probably do not salvage
enough tissue to improve clinical outcome.
Follow-up of Treatment Effects
The effectiveness of reperfusion to ischemically compromised tissue can be assessed by ﬂow studies before
and after the treatment and by relating the induced ﬂow
changes to the outcome. Of 100 patients receiving
thrombolytic therapy (according to NINDS study protocol),14 15 patients were admitted during the working
hours of the PET unit, and in 12 of them CBF could bestudied repeatedly and the ﬂow changes could be related to the clinical course (followed by the NIH Stroke
Scale) and to the morphological damage demarcated on
MRI 3 weeks after the stroke.21 The ﬁrst CBF study
was performed right before or during the ﬁrst 10 min of
rt-PA infusion, CBF was re-assessed approximately 2 h
and again 18–28 h after the end of that infusion. Since
the contraindication for arterial blood sampling prevented quantitative determinations relative regional
tracer uptake was used to estimate the level of residual
blood ﬂow in the affected hemisphere. The threshold of
severe hypoperfusion in gray matter was operationally
set to 50% ( 15 O)-H2 O uptake relative to the mean of
the contralateral hemisphere, which corresponded to agray matter blood ﬂow of approx. 12 ml/100 g/min20
which represents a widely accepted viability threshold.3,4 Hence, gray matter voxels showing only 50% orless uptake on ﬁrst measurement were considered critically hypoperfused and threatened by infarction. The
tissue compartments deﬁned at ﬁrst measurement were
followed in the subsequent measurements and compared to the MRI at 3 weeks on which the extent of the
ﬁnal infarct was outlined.
In this small sample patients with a severely hypoperfused (<12 ml/100 g/min) gray-matter region measuring less than 15 cm 3 on ﬁrst PET showed full morphological and clinical recovery ðn ¼ 5Þ, while thosewith ischemic areas larger than 20 cm 3 developed
infarction and suffered persistent neurologic deﬁcits ofvarying degree (Fig. 3). Infarct sizes, however, were
smaller than expected from previous correlative PET
and morphological studies of patients with acute stroke:
only 22.7% of the gray matter initially perfused at rates
below the conventional threshold of critical ischemia
became necrotic. Actually, the percentage of initially
ischemic voxels that became reperfused at almost normal levels clearly predicted the degree of clinical improvement achieved within three weeks.

Keio J Med 2001; 50 (4): 249–256

These sequential blood ﬂow studies demonstrate thatcritically hypoperfused tissue can be preserved by earlyreperfusion eventually induced by thrombolytic therapy(Fig. 2). The data support the results of the clinical trials
and extend the recent observation by Grotta and Alexandrov22 by identifying the portions of compromised
tissue that become reperfused and do not proceed toinfarction.
Markers for Early Detection of Irreversibly
Damaged Tissue
For planning treatment of acute ischemic stroke asingle marker of neuronal integrity would be extremely
helpful, which could distinguish permanently damaged
from functionally impaired tissue. Central benzodiazepine receptor (BZR) ligands were suggested by Sette,
et al.23 for that purpose, since they mark intact corticalneurons and therefore could delineate early neuronaldamage. Labeled BZR ligands were successfully used
for the separation between infarcted and deactivatedtissue after stroke.24,25 In transient MCA occlusion in
11 cats the development of the defects in energy metabolism was compared to the defects of the binding of
11
C-ﬂumazenil (FMZ) and to the size of the infarcts
determined 15 hours after MCAO.12 Irrespective ofthe level of reperfusion, defects in FMZ binding 2–3 hafter MCAO were closely related to areas with severely
depressed oxygen consumption and predicted the sizeof the ﬁnal infarcts whereas preserved FMZ binding
indicated intact cortex. Depressed glucose metabolism
outside the areas of reduced FMZ binding – and outside the ﬁnal infarcts – indicated functional inactivation. Additionally, FMZ distribution within 2 min after
injection was signiﬁcantly correlated to ﬂow and therefore can be used as a relative ﬂow tracer yielding reliable perfusion images.
These strategies were applied in 10 patients sufferingfrom acute ischemic attacks within 3–16 h after onsetof symptoms.26 The early changes in ﬂow, oxygen consumption, and FMZ binding were compared to permanent disturbances in glucose metabolism and the size ofthe ﬁnal infarcts determined on MRI or CT 12–22 days
after the stroke. In the 9 patients with focally disturbed
blood ﬂow cortical regions with reduced FMZ binding
predicted the ﬁnal infarcts or areas with severely depressed glucose metabolism indicative of marked neuronal loss. The predictive value of reduced FMZ binding was comparable to that of a focal CMRO 2 reduction
below 60 mmol/100 g/min, but the BZR ligand study
does not necessitate arterial puncture and cooperationof patients, has the advantage of superior image quality
and the potential of SPECT application. Additionally,
perfusion can be assessed by following the early distri-

253

bution of the same tracer. Overall, these results demonstrate that BZR radioligands – FMZ for PET, 123 Iiomazenil for SPECT – have a potential as clinicallyuseful tracers in patients with acute ischemic stroke.
In another study27 the multitracer approach was utilized to identify the area of irreversible damage and to
distinguish it from the penumbral zone. Ten patients(seven male, three female, aged 52–75 years) with acuteischemic stroke, in whom MRI delineated an infarct involving the cortex 3 weeks after the attack, were studied
by [ 11 C]ﬂumazenil (FMZ) PET to assess their neuronal
integrity, and regional CBF was measured by H2 15 O
PET 2–12 h (median interval 6 h) after onset of symptoms. Cortical volumes of interest (3 mm radius) wereplaced on co-registered CBF, FMZ and on late MRI
scans. Using initial CBF and FMZ binding data fromvolumes of interest ﬁnally located within or outside thecortical infarct, cumulative probability curves were computed to predict eventual infarction or non-infarction.
Positive (at least 95% chance of infarct) and negative(at least 95% chance of non-infarct) prediction limits
for CBF (4.8 and 14.1 ml/100 g/min, respectively) andfor FMZ binding (3.4 and 5.5 times the mean of normal
white matter, respectively) were determined to deﬁne
the penumbral range (Fig. 4). Using the lower FMZ
binding threshold of 3.4 for irreversible tissue damage
and the upper CBF value of 14.1 ml/100 g/min for thethreshold of critical perfusion at or above which tissue

Fig. 4 Left: weighted mean curves across all patients’ volumes of interest and corresponding 95% probability limits, predicting cortical
infarction ( positive prediction curve) or non-infarction (negative prediction curve) from early relative CBF: lower endpoints of curves denote proportion of non-infarcted and infarcted tissue, respectively, as
present in the analyzed sample. Right: weighted mean curves acrossall patients’ volumes of interest, and corresponding 95% probability
limits, predicting cortical infarction ( positive prediction curve) or
non-infarction (negative prediction curve) from early relative FMZ
binding. Lower endpoints of curves denote proportion on noninfarcted and infarcted tissue, respectively, as present in the analyzed
sample.

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Fig. 5 Various subcompartments in and outside the ﬁnal infarct ofpatient 2. (A) Extension of ﬁnal infarct. (B) Compartment with initial
FMZ binding decreased to <3.4 times the contralateral oval centre
value. (C ) Compartment with initial ﬂow decreased to <14.1 ml/100 g/
min. (D) Combination of A, B and C, showing subcompartments ofdecreased FMZ binding and decreased ﬂow in relation to ﬁnal infarct.

will likely be preserved, various cortical subcompartments were identiﬁed (Fig. 5): of the ﬁnal cortical infarct (median size 25.7 cm 3 ) a major portion comprising, on average, 55.1% showed FMZ binding criticallydecreased, thus predicting necrosis. In 20.5% of the
ﬁnal infarct, on average, CBF was in the penumbral
range (< 14.1 ml/100 g/min) and FMZ binding wasabove the critical threshold of irreversible damage.
Only 12.9% of the ﬁnal infarct exhibited neuronal integrity and CBF values above the penumbral range.
Therefore, most of the ﬁnal infarct is irreversibly damaged already at the time of the initial evaluation, whenstudied several hours after stroke onset. A much smaller
portion is still viable but suffers from insufﬁcient blood
supply: this tissue may be salvaged by effective reperfusion. Only an even smaller compartment is viable andsufﬁciently perfused, but eventually becomes necrotic,
mainly owing to delayed mechanisms, and may beneﬁt
from neuroprotective or other measures targeted atsecondary damage. Therefore, early reperfusion is crucial in acute ischemic stroke.
That BZR radioligands actually can be used to selectpatients who might beneﬁt from a therapeutic intervention was shown in another study of 10 patients withacute hemispheric stroke in whom thrombolysis14 was

Heiss W-D: PET of ischemic penumbra

Fig. 6 Effect of rtPA treatment in two patients with large ischemic
areas (white arrows): patient 6 ( pat06) with area of decreased FMZ
binding (blue arrow) and corresponding large infarction on late cranial CT (red arrow), and patient 2 ( pat02) with no defect in FMZ
binding and no infarcted cortex on late cranial CT.

started within 3 hours of symptoms onset.28 At the beginning of thrombolysis ﬂow and FMZ binding wereassessed by PET, and the early PET ﬁndings were related to change in neurologic deﬁcits and to the extent
of morphologic damage on MRI or CT 3 weeks after
the stroke. Hypoperfusion was observed in all cases andin 7 patients the values were below critical thresholds
estimated at 12 ml/100 g/min in variable volumes of 1–
174 ml. Reperfusion was seen in most of these regions
24 hours after thrombolysis. In 3 cases, distinct areas
with decreased FMZ binding were detected. These 3
patients suffered from permanent lesions in corticalareas corresponding to the FMZ defects (112 vs 146, 3
vs 3, and 1.7 vs 0.7 ml) (Fig. 6). In the other patients nomorphological defects were detected on MRI or CT,
although ﬂow was critically decreased before thrombolysis in large areas (53 and 78 ml) in 2 patients and insmaller regions (1–7 ml) in 3 patients (Fig. 6). Theseﬁndings suggest that imaging of benzodiazepine receptors by FMZ-PET distinguishes between irreversibly
damaged and viable penumbra tissue early after acutestroke and can be used to identify patients who will
beneﬁt from interventional therapy.
Consequences for Stroke Management
The importance of the early perfusional deﬁcit forthe development of infarction and the short window ofopportunity for reperfusion therapy stress the need of
efﬁcient and fast management of patients with acuteKeio J Med 2001; 50 (4): 249–256

255

6.

7.

8.

9.

10.
Fig. 7 Modiﬁed Rankin Scale scores at 3 and 12 months in patientstreated in Cologne compared with patients from the NINDS rtPA
Stroke Trial placebo and treatment groups (3 and 12 months) andwith the ECASS I and ECASS II 3 h rtPA cohorts (3 months).
11.

ischemic stroke. A cooperative initiative in the City of
Cologne combining the task forces of 2 Neurological
Departments, 14 Medical Departments in City Hospitals and the Emergency System made it possible to submit close to 40% of patients with suspected stroke tohospital treatment within 3 h of symptoms onset and to
apply systemic rt-PA treatment to a rather large patientgroup (approx. 300 patients treated within 5.5 years).
The results obtained are similar to those of multicenter
trials14,29,30 with 39% of patients with no or minimal
deﬁcit after 3 months31 and 40% with no or minimal
deﬁcit after 1 year32 (comparable to the NINDS followup study by Kwiatkowski, et al.)33 (Fig. 7). These data
impressively support the impact of the penumbra forpotentially effective treatment of stroke and the importance of fast and effective management of stroke victims.
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