Textbook of Stroke Medicine, 2E (2013)

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Textbook of Stroke Medicine
Second Edition
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Textbook of Stroke Medicine
Second Edition
Edited by
Michael Brainin MD PhD
Professor and Chair, Department of Clinical Neuroscience and Preventive Medicine,
Danube University Krems, Krems, Austria
Wolf-Dieter Heiss MD PhD
Professor of Neurology, Emeritus Director, Max Planck Institute for Neurological Research and
Department of Neurology, University of Cologne, Cologne, Germany
Editorial Assistant
Susanne Tabernig MD
Vienna, Austria
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Library of Congress Cataloging in Publication data
Textbook of stroke medicine / edited by Michael Brainin,
Wolf-Dieter Heiss ; editorial assistant, Suzanne Tabernig. –
Second edition.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-107-04749-5
I. Brainin, M. (Michael), editor of compilation. II. Heiss, W.-D.
(Wolf-Dieter), 1939 December 31- editor of compilation.
III. Tabernig, Suzanne, editor of compilation.
[DNLM: 1. Stroke. WL 355]
RC388.5
616.801–dc23 2013048020
Michael Brainin & Wolf-Dieter Heiss 
 
2013 
 
ISBN-13: 9781107047495
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Contents
List of contributors vii
Preface ix
Section 1 – Etiology, pathophysiology,
and imaging
1. Neuropathology and pathophysiology of
stroke 1
Konstantin-A. Hossmann and Wolf-Dieter Heiss
2. Common causes of ischemic stroke 33
Bo Norrving
3. Neuroradiology 45
(A) Imaging of acute ischemic and
hemorrhagic stroke: CT, perfusion CT, CT
angiography 45
Patrik Michel
(B) Imaging of acute ischemic and
hemorrhagic stroke: MRI and MR
angiography 49
Jochen B. Fiebach, Patrik Michel, and Jens Fiehler
(C) Multimodal imaging-guided acute
stroke treatment based on CT and MR
imaging 54
Patrik Michel
4. Imaging for prediction of functional
outcome and for assessment of recovery 64
Wolf-Dieter Heiss
5. Ultrasound in acute ischemic stroke 82
László Csiba
Section 2 – Clinical epidemiology
and risk factors
6. Basic epidemiology of stroke and risk
assessment 102
Jaakko Tuomilehto
7. Common risk factors and prevention 119
Michael Brainin, Yvonne Teuschl, and Karl Matz
8. Cardiac diseases relevant to
stroke 140
Claudia Stöllberger and Josef Finsterer
Section 3 – Diagnostics and
syndromes
9. Common stroke syndromes 155
Céline Odier and Patrik Michel
10. Less common stroke syndromes 169
Wilfried Lang
11. Intracerebral hemorrhage 188
Corina Epple, Michael Brainin, and Thorsten
Steiner
12. Subarachnoid hemorrhage 206
Philipp Lichti and Thorsten Steiner
13. Cerebral venous thrombosis 222
Jobst Rudolf
14. Behavioral neurology of stroke 236
José M. Ferro, Isabel P. Martins, and
Lara Caeiro
15. Stroke and dementia 255
Barbara Casolla and Didier Leys
16. Ischemic stroke in the young and in
children 266
Valeria Caso and Didier Leys
Section 4 – Therapeutic strategies
and neurorehabilitation
17. Stroke units and clinical assessment 285
Danilo Toni and Ángel Chamorro
18. Acute therapies for stroke 294
Richard E. O’Brien and Kennedy R. Lees
v
19. Interventional intravascular therapies for
stroke 311
Pasquale Mordasini, Jan Gralla, and Gerhard
Schroth
20. Management of acute ischemic stroke and
its late complications 326
Natan M. Bornstein and Eitan Auriel
21. Infections in stroke 342
Achim J. Kaasch and Harald Seifert
22. Secondary prevention 356
Hans-Christoph Diener, Sharan K. Mann,
and Gregory W. Albers
23. Neurorehabilitation practice for stroke
patients 371
Sylvan J. Albert and Jürg Kesselring
Index 399
Contents
vi
Contributors
Gregory W. Albers, MD
Department of Neurology, Stanford University
Medical Center, Stanford, CA, USA
Sylvan J. Albert, MD, MSc
Department of Neurology and Neurorehabilitation,
Rehabilitation Centre, Valens, Switzerland
Eitan Auriel, MD
Department of Neurology, Elias Sourasky Medical
Centre, Tel-Aviv, Israel
Natan M. Bornstein, MD
Department of Neurology, Elias Sourasky Medical
Centre, Sackler Faculty of Medicine, Tel-Aviv
University, Tel-Aviv, Israel
Michael Brainin, MD, PhD
Department of Clinical Neuroscience and
Preventive Medicine, Danube University Krems,
Krems, Austria
Lara Caeiro, PhD, Mcs
Department of Neurosciences, Hospital de Santa
Maria and Instituto de Medicina Molecular,
University of Lisboa, Portugal
Valeria Caso, MD, PhD
Department of Internal Medicine, Stroke Unit,
University of Perugia, Perugia, Italy
Barbara Casolla, MD
Department of Neurology, Sapienza University,
Rome, Italy
Ángel Chamorro, MD, PhD
Neurology Service, Jefe dela Unidad de Ictus Hospital
Clinico, Barcelona, Spain
László Csiba, MD, PhD, DSc
Department of Neurology, University of Debrecen,
Health Science Center, Debrecen, Hungary
Hans-Christoph Diener, MD, PhD
Department of Neurology, University Hospital Essen,
University Duisberg Essen, Germany
Corina Epple, MD
Department of Neurology, Klinikum Frankfurt
Höchst, Frankfurt, Germany
José M. Ferro, MD, PhD
Department of Neurosciences, Hospital de Santa
Maria and Instituto de Medicina Molecular,
University of Lisboa, Portugal
Jochen B. Fiebach, MD
Department of Neurology, Center for Stroke
Research Berlin, Charité-Universitätsmedizin Berlin,
Berlin, Germany
Jens Fiehler, MD
Department of Diagnostic and Interventional
Neuroradiology, University Medical Center
Hamburg-Eppendorf, Hamburg, Germany
Josef Finsterer, MD, PhD
Department of Internal Medicine, Krankenanstalt
Rudolfstiftung, Vienna, Austria
Jan Gralla, MD, MSc
University Institute of Diagnostic and Interventional
Neuroradiology, Inselspital, University of Bern, Bern,
Switzerland
Wolf-Dieter Heiss, MD, PhD
Max Planck Institute for Neurological Research and
Department of Neurology, University of Cologne,
Cologne, Germany
Konstantin-A. Hossmann, MD, PhD
Max Planck Institute for Neurological Research,
Cologne, Germany
vii
Achim J. Kaasch, MD
Institute for Medical Microbiology, Immunology
and Hygiene, Medical Center, University of Cologne,
Cologne, Germany
Jürg Kesselring, MD
Department of Neurology and Neurorehabilitation,
Rehabilitation Centre, Valens, Switzerland
Wilfried Lang, MD
Neurologische Abteilung, KH der Barmherzigen
Brüder Wien, Vienna, Austria
Kennedy R. Lees, MD
Division of Cardiovascular and Medical Sciences,
University of Glasgow and Western Infirmary,
Glasgow, UK
Didier Leys, MD, PhD
Department of Neurology, Stroke Department,
University of Lille, Lille, France
Philipp Lichti, MD
Department of Neurology, Klinikum Frankfurt
Höchst, Frankfurt, Germany
Sharan K. Mann, MD
Department of Neurology, Stanford University
Medical Center, Stanford, CA, USA
Isabel P. Martins, MD, PhD
Department of Neurosciences, Hospital de Santa
Maria and Instituto de Medicina Molecular,
University of Lisboa, Portugal
Karl Matz, MD
Department of Neurology, Landesklinikum Tulln,
Tulln, Austria
Patrik Michel, MD
Neurology Service, Centre Hospitalier Universitaire
Vaudois, University of Lausanne, Lausanne,
Switzerland
Pasquale Mordasini, MD, MSc
University Institute of Diagnostic and Interventional
Neuroradiology, Inselspital, University of Bern, Bern,
Switzerland
Bo Norrving, MD, PhD
Department of Clinical Sciences, Division of
Neurology, Lund University, Sweden
Richard E. O’Brien, MD, FRCPEdin, MBChB
City Hospitals Sunderland NHS Foundation Trust,Sunderland Royal Hospital, Sunderland, UK
Céline Odier, MD
Neurology Service, Centre Hospitalier Universitaire
Vaudois, University of Lausanne, Lausanne, Switzerland
Jobst Rudolf, MD, PhD
Department of Neurology, General Hospital
“Papageorgiou,” Thessaloniki, Greece
Gerhard Schroth, MD
University Institute of Diagnostic and Interventional
Neuroradiology, Inselspital, University of Bern, Bern,
Switzerland
Harald Seifert, MD
Institute for Medical Microbiology, Immunology and
Hygiene, University of Cologne, Cologne, Germany
Thorsten Steiner, MD, PhD, MME
Department of Neurology, Klinikum Frankfurt
Höchst, Frankfurt, Germany and Department of
Neurology, University of Heidelberg, Heidelberg,
Germany
Claudia Stöllberger, MD
Department of Internal Medicine, Krankenanstalt
Rudolfstiftung, Vienna, Austria
Yvonne Teuschl, PhD
Department for Clinical Neurosciences and
Preventive Medicine, Danube University Krems,
Krems, Austria
Danilo Toni, MD
Emergency Department Stroke Unit, Department of
Neurological Sciences, University “La Sapienza,”
Rome, Italy
Jaakko Tuomilehto, MD, PhD
Centre for Vascular Prevention, Danube University
Krems, Krems, Austria;
Diabetes Prevention Unit, National Institute for
Health and Welfare, Helsinki, Finland;
King Abdulaziz University, Jeddah,
Saudi Arabia; and
Instituto de Investigacion Sanitaria del
Hospital Universario LaPaz (IdiPAZ),
Madrid, Spain
List of contributors
viii
Preface
This book is designed to improve the teaching and
learning of stroke medicine in postgraduate educa-
tional programs. It is targeted at “beginning special-
ists,” either medical students with a deeper interest or
medical doctors entering the field of specialized
stroke care. Therefore, the text contains what is con-
sidered essential for this readership but, in addition,
goes into much greater depth, e.g. the coverage of less
frequent causes of stroke, and describing the more
technical facets and settings of modern stroke care.
The textbook leads the reader through the many
causes of stroke, its typical manifestations, and the
practical management of the stroke patient. We have
tried to keep the clinical aspects to the fore, giving
relative weight to those chapters that cover clinically
important issues; however, the pathological, patho-
physiological and anatomical background is included
where necessary. The book benefits from the experi-
ence of many specialized authors, thereby providing
expert coverage of the various topics by international
authorities in the field. In places this leads to some
differences of opinion in the approach to particular
patients or conditions; as editors we have tried not
to interfere with the individual character of each
chapter, leaving only duplicate presentations when
they were handled from different topological or
didactic aspects, e.g. on genetic or rarer forms of
diseases.
The development of this textbook has been trig-
gered by the “European Master in Stroke Medicine
Programme” held at Danube University in Austria.
This program has been fostered by the European
Stroke Organisation and has been endorsed by the
World Stroke Organization. This book has been
shaped by the experiences of the lecturers – most of
them also leading authors for our chapters – and the
feedback of our students during several runs of this
course. Thus, we hope to satisfy the needs of students
and young doctors from many different countries,
both within and outside Europe.
Finally, we would like to thank Dr. Susanne Taber-
nig for her expert editorial assistance and her diligent
and expert help in summarizing the chapters’ contents.
Thanks also to Nick Dunton and his team at
CambridgeUniversity Press for their help and patience.
Michael Brainin
Wolf-Dieter Heiss
ix
Section 1
Chapter
1
Etiology, pathophysiology, and imaging
Neuropathology and pathophysiology
of stroke
Konstantin-A. Hossmann andWolf-Dieter Heiss
The vascular origin of cerebrovascular
disease
All cerebrovascular diseases (CVDs) have their origin
in the vessels supplying or draining the brain. There-
fore, the knowledge of pathological changes occurring
in the vessels and in the blood are essential for under-
standing the pathophysiology of the various types of
CVD and for planning of efficient therapeutic strat-
egies. Changes in the vessel wall lead to obstruction of
blood flow, by interacting with blood constituents
they may cause thrombosis and blockade of blood
flow in this vessel. In addition to vascular stenosis or
occlusion at the site of vascular changes, disruption of
blood supply and consecutive infarcts can also be
produced by emboli arising from vascular lesions
situated proximally to otherwise healthy branches
located more distal in the arterial tree or from a
source located in the heart. At the site of occlusion,
opportunity exists for thrombus to develop in ante-
rograde fashion throughout the length of the vessel,
but this event seems to occur only rarely.
Changes in large arteries supplying the brain,
including the aorta, are mainly caused by atheroscler-
osis. Middle-sized and intracerebral arteries can also
be affected by acute or chronic vascular diseases of
inflammatory origin due to subacute to chronic infec-
tions, e.g. tuberculosis and lues, or due to collagen
disorders, e.g. giant cell arteritis, granulomatous
angiitis of the central nervous system, panarteritis
nodosa, and even more rarely systemic lupus erythe-
matosus, Takayasu’s arteritis, Wegener granulomato-
sis, rheumatoid arteritis, Sjögren’s syndrome, or
Sneddon and Behçet’s disease. In some diseases
affecting the vessels of the brain the etiology and
pathogenesis are still unclear, e.g. moyamoya disease
and fibromuscular dysplasia, but these disorders are
characterized by typical locations of the vascular
changes. Some arteriopathies are hereditary, such as
CADASIL (cerebral autosomal dominant arteriopa-
thy with subcortical infarcts and leukoencephalopa-
thy), in some such as cerebral amyloid angiopathy a
degenerative cause has been suggested. All these vas-
cular disorders can cause obstruction, and lead to
thrombosis and embolizations. Small vessels of the
brain are affected by hyalinosis and fibrosis; this
“small-vessel disease” can cause lacunes and, if wide-
spread, is the substrate for vascular cognitive impair-
ment and vascular dementia.
Atherosclerosis is the most widespread disorder
leading to death and serious morbidity including
stroke [1]. The basic pathological lesion is the ather-
omatous plaque, and the most commonly affected
sites are the aorta, the coronary arteries, the carotid
artery at its bifurcation, and the basilar artery.
Arteriosclerosis, a more generic term describing
hardening and thickening of the arteries, includes as
additional types Mönkeberg’s sclerosis which is char-
acterized by calcification in the tunica media and
arteriolosclerosis with proliferative and hyaline
changes affecting the arterioles. Atherosclerosis starts
at young age, lesions accumulate and grow through-
out life and become symptomatic and clinically evi-
dent when end organs are affected [2].
Atherosclerosis: atheromatous plaques, most commonly
in the aorta, the coronary arteries, the bifurcation of the
carotid artery and the basilar artery.
The initial lesion of atherosclerosis has been attrib-
uted to “fatty streaks” and the “intimal cell mass.”
Those changes already occur in childhood and ado-
lescence and do not necessarily correspond to the
future sites of atherosclerotic plaques. Fatty streaks
Textbook of Stroke Medicine, Second Edition, ed. Michael Brainin and Wolf-Dieter Heiss. Published by Cambridge University
Press. © Michael Brainin and Wolf-Dieter Heiss 2014.
1
are focal areas of intra cellular lipid collection in both
macrophages and smooth muscle cells. Various con-
ceptshave been proposed to explain the progression
of such precursor lesions to definite atherosclerosis
[2, 3], most remarkable of which is the response-to-
injury hypothesis postulating a cellular and molecular
response to various atherogenic stimuli in the form of
an inflammatory repair process [4]. This inflamma-
tion develops concurrently with the accumulation of
minimally oxidized low-density lipoproteins (LDLs)
[5, 6], and stimulates vascular smooth muscle cells
(VSMCs), endothelial cells, and macrophages [7], and
as a result foam cells aggregate with an accumulation
of oxidized LDL. In the further stages of arthero-
sclerotic plaque development VSMCs migrate, prolif-
erate, and synthesize extracellular matrix components
on the luminal side of the vessel wall, forming the
fibrous cap of the atherosclerotic lesion [8]. In this
complex process of growth, progression, and finally
rupture of an atherosclerotic plaque a large number of
matrix modulators, inflammatory mediators, growth
factors, and vasoactive substances are involved. The
complex interactions of these many factors are dis-
cussed in the special literature [5–9].
The fibrous cap of the atherosclerotic lesion
covers the deep lipid core with a massive accumula-
tion of extracellular lipids (atheromatous plaque), or
fibroblasts and extracellular calcifications may con-
tribute to a fibrocalcific lesion. Mediators from inflam-
matory cells at the thinnest portion of the cap surface
of a vulnerable plaque – which is characterized by a
larger lipid core and a thin fibrous cap – can lead to
plaque disruption with formation of a thrombus or
hematoma or even to total occlusion of the vessel.
During the development of atherosclerosis the entire
vessel can enlarge or constrict in size [10]. However,
once the plaque covers >40% of the vessel wall, the
artery no longer enlarges, and the lumen narrows as
the plaque grows. In vulnerable plaques thrombosis
forming on the disrupted lesion further narrows
the vessel lumen and can lead to occlusion or be
the origin of emboli. Less commonly, plaques
have reduced collagen and elastin with a thin and
weakened arterial wall, resulting in aneurysm forma-
tion which when ruptured may be the source of
intracerebral hemorrhage (Figure 1.1).
Injury hypothesis of progression to atherosclerosis: fatty
streaks (focal areas of intra cellular lipid collection) !
inflammatory repair process with stimulation of vascular
smooth muscle cells ! atheromatous plaque.
Thromboembolism: immediately after plaque rupture
or erosion, subendothelial collagen, the lipid core, and
procoagulants such as tissue factor and von Wille-
brand factor are exposed to circulating blood. Platelets
rapidly adhere to the vessel wall through the platelet
glycoproteins (GP) Ia/IIa and GP Ib/IX [11] with
subsequent aggregation to this initial monolayer
through linkage with fibrinogen and the exposed GP
IIb/IIIa on activated platelets. As platelets are a source
of nitric oxide (NO), the resulting deficiency of bioac-
tive NO, which is an effective vasodilator, contributes
Figure 1.1. The stages of development of an atherosclerotic plaque. (1) LDL moves into the subendothelium and (2) is oxidized by
macrophages and smooth muscle cells (SMC). (3) Release of growth factors and cytokines (4) attracts additional monocytes. (5) Macrophages
and (6) foam cell accumulation and additional (7) SMC proliferation result in (8) growth of the plaque. (9) Fibrous cap degradation and plaque
rupture (collagenases, elastases). (10) Thrombus formation. IL-1 ¼ interlenkin-1; MCP-1 ¼ Monocyte chemotactic protein-1. (Modified with
permission from Faxon et al. [5].)
Section 1: Etiology, pathophysiology, and imaging
2
to the progression of thrombosis by augmenting
platelet activation, enhancing VSMC proliferation
and migration, and participating in neovasculariza-
tion [12]. The activated platelets also release adeno-
sine diphosphate (ADP) and thromboxane A2 with
subsequent activation of the clotting cascade. The
growing thrombus obstructs or even blocks the
blood flow in the vessel. Atherosclerotic thrombi
are also the source for embolisms, which are the
primary pathophysiological mechanism of ischemic
strokes, especially from carotid artery disease or of
cardiac origin.
Rupture or erosion of atheromatous plaques! adhesion
of platelets ! thrombus ! obstruction of blood flow
and source of emboli.
Small-vessel disease usually affects the arterioles and is
associated with hypertension. It is caused by suben-
dothelial accumulation of a pathological protein, the
hyaline, formed from mucopolysaccharides and
matrix proteins, which leads to narrowing of the
lumen or even occlusion of these small vessels. Often
it is associated with fibrosis, which affects not only
arterioles, but also other small vessels and capillaries
and venules. Lipohyalinosis also weakens the vessel
wall, predisposing for the formation of “miliary
aneurysms.” Small-vessel disease results in two patho-
logical conditions: status lacunaris (lacunar state) and
status cribrosus (état criblé). Status lacunaris is char-
acterized by small irregularly shaped infarcts due to
occlusion of small vessels; it is the pathological sub-
strate of lacunar strokes and vascular cognitive
impairment and dementia. In status cribrosus small
round cavities develop around affected arteries due
to disturbed supply of oxygen and metabolic sub-
strate. These “criblures” together with miliary aneur-
ysms are the sites of vessel rupture causing typical
hypertonic intracerebral hemorrhages [13–16].
A second type of small-vessel disease is characterized
by the progressive accumulation of congophilic, βA4
immunoreactive, amyloid protein in the walls of
small- to medium-sized arteries and arterioles. Cere-
bral amyloid angiopathy is a pathological hallmark
of Alzheimer’s disease and also occurs in rare genet-
ically transmitted diseases, e.g. CADASIL and Fabry’s
disease [17]. For a more detailed discussion of the
etiology and pathophysiology of the various specific
vascular disorders see [18–20].
Small-vessel disease: subendothelial accumulation of
hyaline in arterioles.
Types of acute cerebrovascular diseases
Numbers relating to the frequency of the different
types of acute CVD are highly variable depending
on the source of data. The most reliable numbers
come from the in-hospital assessment of stroke in
the Framingham study determining the frequency
of completed stroke: 60% were caused by athero-
thrombotic brain infarction, 25.1% by cerebral
embolism, 5.4% by subarachnoid hemorrhage,
8.3% by intracerebral hemorrhage, and 1.2% by
undefined diseases. In addition, transient ischemic
attacks (TIAs) accounted for 14.8% of the total
cerebrovascular events [21].
Ischemic strokes result from a critical reduction of
regional cerebral blood flow (rCBF) lasting beyond a
critical duration, and are caused by atherothrombotic
changes of the arteries supplying the brain or by
emboli from sources in the heart, the aorta, or the
large arteries. The pathological substrate of ischemic
stroke is ischemic infarction of brain tissue, the loca-
tion, extension, and shape of which depend on the
size of the occluded vessel, the mechanism of arterial
obstruction, and the compensatory capacity of the
vascular bed. Occlusion of arteries supplying defined
brain territories by atherothrombosis or embolization
lead to territorial infarcts of variable size: they may be
large – e.g. the whole territory supplied by the middle
cerebral artery (MCA) – or small, if branches of large
arteries are occluded or if compensatory collateral
perfusion – e.g. via the circle of Willis or leptomenin-
geal anastomoses – is efficient in reducing the area of
critically reduced flow (Figure 1.2) [14, 16]. In a
smaller number of cases infarcts can also develop at
the borderzones between vascular territories,when
several large arteries are stenotic and the perfusion
in these “last meadows” cannot be constantly main-
tained above the critical threshold of morphological
integrity [22]. Borderzone infarctions are a subtype of
the low-flow or hemodynamically induced infarctions
which are the result of critically reduced cerebral
perfusion pressure in far-downstream brain arteries.
The more common low-flow infarctions affect sub-
cortical structures within a vascular bed with pre-
served but marginal irrigation [23]. Lacunar infarcts
reflect disease of the vessels penetrating the brain to
supply the capsule, the basal ganglia, thalamus, and
paramedian regions of the brainstem [24]. Most often
they are caused by lipohyalinosis of deep arteries
(small-vessel disease); less frequent causes are stenosis
Chapter 1: Neuropathology and pathophysiology of stroke
3
of the MCA stem and microembolization to penetrant
arterial territories. Pathologically these lacunes are
defined as small cystic trabeculated scars about
5 mm in diameter, but they are more often observed
on magnetic resonance images, where they are
accepted as lacunes up to 1.5 cm diameter. The classic
lacunar syndromes include pure motor, pure sensory,
and sensorimotor syndromes, sometimes ataxic hemi-
paresis, clumsy hand, dysarthria, and hemichorea/
hemiballism, but higher cerebral functions are not
involved. A new classification of stroke subtypes is
mainly oriented on the most likely cause of stroke:
atherosclerosis, small-vessel disease, cardiac source,
or other cause [25].
Territorial infarcts are caused by an occlusion of arteries
supplying defined brain territories by atherothrombosis
or embolizations.
Borderzone infarcts develop at the borderzone between
vascular territories and are the result of a critically
reduced cerebral perfusion pressure (low-flow
infarctions).
Lacunar infarcts are mainly caused by small-vessel
disease.
Hemorrhagic infarctions, i.e. “red infarcts” in contrast
to the usual “pale infarcts,” are defined as ischemic
infarcts in which varying numbers of blood cells are
found within the necrotic tissue. The size can range
from a few petechial bleeds in the gray matter of
cortex and basal ganglia to large hemorrhages involv-
ing the cortical and deep hemispheric regions. Hem-
orrhagic transformation frequently appears during
the second and third phase of infarct evolution, when
macrophages appear and new blood vessels are
formed in tissue consisting of neuronal ghosts and
proliferating astrocytes. However, the only significant
difference between “pale” and “red infarcts” is the
intensity and extension of the hemorrhagic compon-
ent, since in at least two-thirds of all infarcts petechial
hemorrhages are microscopically detectable. Macro-
scopically, red infarcts contain multifocal bleedings
which are more or less confluent and predominate
in cerebral cortex and basal ganglia, which are richer
in capillaries than the white matter[26]. If the hemor-
rhages become confluent intrainfarct hematomas
might develop, and extensive edema may contribute
to mass effects and lead to malignant infarction. The
frequency of hemorrhagic infarctions in anatomical
studies ranged from 18% to 42% [27], with a high
incidence (up to 85% of hemorrhagic infarcts) in
cardioembolic stroke [28].
Figure 1.2. Various types and sizes of infarcts due to different hemodynamic patterns
a. Total territorial infarct due to defective collateral supply
b. Core infarct, meningeal anastomosis supply peripheral zones
c. Territorial infarct in center of supply area, due to branch occlusion
d. Borderzone infarction in watershed areas due to stenotic lesions in arteries supplying neighboring areas
e. Lacunar infarctions due to small-vessel disease. (Modified with permission from Zülch [14].)
Section 1: Etiology, pathophysiology, and imaging
4
Mechanisms for hemorrhagic transformation are
manifold and vary with regard to the intensity of
bleeding. Petechial bleeding results from diapedesis
rather than vascular rupture. In severe ischemic tissue
vascular permeability is increased and endothelial
tight junctions are ruptured. When blood circulation
is spontaneously or therapeutically restored, blood
can leak out of these damaged vessels. This can also
happen with fragmentation and distal migration of
an embolus (usually of cardiac origin) in the damaged
vascular bed, explaining delayed clinical worsening
in some cases. For the hemorrhagic transformation
the collateral circulation might also have an impact:
in some instances reperfusion via pial networks
may develop with the diminution of peri-ischemic
edema at borderzones of cortical infarcts. Risk
of hemorrhage is significantly increased in large
infarcts, with mass effect supporting the importance
of edema for tissue damage and the deleterious
effect of late reperfusion when edema resolves. In
some instances also the rupture of the vascular wall
secondary to ischemia-induced endothelial necrosis
might cause an intra-infarct hematoma. Vascular
rupture can explain very early hemorrhagic infarcts
and early intrainfarct hematoma (between 6 and
18 hours after stroke), whereas hemorrhagic trans-
formation usually develops within 48 hours to 2
weeks.
Hemorrhagic infarctions are defined as ischemic infarcts
in which varying amounts of blood cells are found
within the necrotic tissue. They are caused by leakage
from damaged vessels, due to increased vascular
permeability in ischemic tissue or vascular rupture
secondary to ischemia
Intracerebral hemorrhage (ICH) occurs as a result of
bleeding from an arterial source directly into the
brain parenchyma and accounts for 5–15% of all
strokes [29, 30]. Hypertension is the leading risk
factor, but in addition advanced age, race and also
cigarette smoking, alcohol consumption, and high
serum cholesterol levels have been identified. In a
number of instances ICH occurs in the absence of
hypertension, usually in atypical locations. The causes
include small vascular malformations, vasculitis,
brain tumors, and sympathomimetic drugs (e.g.
cocaine). ICH may also be caused by cerebral amyloid
angiopathy and rarely damage is elicited by acute
changes in blood pressure, e.g. due to exposure to
cold. The occurrence of ICH is also influenced
by the increasing use of antithrombotic and
thrombolytic treatment of ischemic diseases of the
brain, heart, and other organs [31, 32].
Spontaneous ICH occurs predominantly in the
deep portions of the cerebral hemispheres (“typical
ICH”) [33]. Its most common location is the putamen
(35–50% of cases). The subcortical white matter is
the second most frequent location (approx. 30%).
Hemorrhages in the thalamus are found in 10–15%,
in the pons in 5–12%, and in the cerebellum in 7%
[34]. Most ICHs originate from the rupture of small,
deep arteries with diameters of 50 to 200 μm which
are affected by lipohyalinosis due to chronic hyper-
tension. These small-vessel changes lead to weakening
of the vessel wall and miliary microaneurysm and
consecutive small local bleedings, which might be
followed by secondary ruptures of the enlarging
hematoma in a cascade or avalanche fashion [35].
After active bleeding has started it can continue
for a number of hours with enlargement of hema-
toma that is frequently associated with clinical
deterioration [36].
Putaminal hemorrhages originate from a lateral
branch of the striate arteries at the posterior angle,
resulting in an ovoid mass pushing the insular cortex
laterally and displacing or involving the internal
capsule. From this initial putaminal-claustral loca-
tion a large hematoma may extend to the internal
capsule and lateral ventricle, into the corona radiata,
and into the temporal white matter. Putaminal
ICHs are considered the typical hypertensive
hemorrhages.
Caudate hemorrhage, a less common formof
bleeding from distal branches of lateral striate arter-
ies, occurs in the head of the caudate nucleus. This
bleeding soon connects to the ventricle and usually
involves the anterior limb of the internal capsule.
Thalamic hemorrhages can involve most of this
nucleus and extend into the third ventricle medially
and the posterior limb of the internal capsule laterally.
The hematoma may press on or even extend into the
midbrain. Larger hematomas often reach the corona
radiata and the parietal white matter.
Lobar (white matter) hemorrhages originate at the
cortico-subcortical junction between gray and white
matter and usually spread along the fiber bundles in
the parietal and occipital lobes. The hematomas are
close to the cortical surface and usually not in direct
contact with deep hemisphere structures or the ven-
tricular system. As atypical ICHs they are not neces-
sarily correlated with hypertension.
Chapter 1: Neuropathology and pathophysiology of stroke
5
Cerebellar hemorrhages usually originate in the
area of the dentate nucleus from rupture of distal
branches of the superior cerebellar artery and extend
into the hemispheric white matter and into the fourth
ventricle. The pontine tegmentum is often com-
pressed. A variant, the midline hematoma, originates
from the cerebellar vermis, always communicates
with the fourth ventricle, and frequently extends
bilaterally into the pontine tegmentum.
Pontine hemorrhages from bleeding of small para-
median basilar perforating branches cause medially
placed hematomas involving the basis of the pons.
A unilateral variety results from rupture of distal
long circumferential branches of the basilar artery.
These hematomas usually communicate with the
fourth ventricle, and extend laterally and ventrally
into the pons.
The frequency of recurrent ICHs in hypertensive
patients is rather low (6%) [37]. Recurrence rate is
higher with poor control of hypertension and also in
hemorrhages due to other causes. In some instances
multiple simultaneous ICHs may occur, but also in
these cases the cause is other than hypertension.
In ICHs, the local accumulation of blood des-
troys the parenchyma, displaces nervous structures,
and dissects the tissue. At the bleeding sites fibrin
globes are formed around accumulated platelets.
After hours or days extracellular edema develops at
the periphery of the hematoma. After 4 to 10 days
the red blood cells begin to lyse, granulocytes and
thereafter microglial cells arrive, and foamy macro-
phages are formed, which ingest debris and hemosi-
derin. Finally, the astrocytes at the periphery of the
hematoma proliferate and turn into gemistocytes
with eosinophylic cytoplasma. When the hematoma
is removed, the astrocytes are replaced by glial
fibrils. After that period – extending to months –
the residue of the hematoma is a flat cavity with a
reddish lining resulting from hemosiderin-laden
macrophages [34].
Intracerebral hemorrhage (ICH) occurs as a result of
bleeding from an arterial source directly into the brain
parenchyma, predominantly in the deep portions of
the cerebral hemispheres (typical ICH). Hypertension
is the leading risk factor, and the most common location
is the putamen.
Cerebral venous thrombosis (CVT) can develop from
many causes and due to predisposing conditions.
CVT is often multifactorial, when various risk factors
and causes contribute to the development of this dis-
order [38]. The incidence of septic CVT has been
reduced to less than 10% of cases, but septic cavernous
sinus thrombosis is still a severe, however, rare prob-
lem. Aseptic CVT occurs during puerperium and less
frequently during pregnancy, but may also be related
to use of oral contraceptives. Among the non-
infectious causes of CVT congenital thrombophilia,
particularly prothrombin and factor V Leiden gene
mutations, as well as antithrombin, protein C, and
protein S deficiencies must be considered. Other con-
ditions with risk for CVT are malignancies, inflamma-
tory diseases, and systemic lupus erythematosus.
However, in 20–35% of CVT the etiology remains
unknown. The fresh venous thrombus is rich in red
blood cells and fibrin and poor in platelets. Later on,
it is replaced by fibrous tissue, occasionally with reca-
nalization. The most common location of CVT is the
superior sagittal sinus and the tributary veins.
Whereas some thromboses, particularly of the
lateral sinus, may have no pathological consequences
for the brain tissue, occlusion of large cerebral veins
usually leads to a venous infarct. These infarcts are
located in the cortex and adjacent white matter and
often are hemorrhagic. Thrombosis of the superior
sagittal sinus may lead only to brain edema, but
usually causes bilateral hemorrhagic infarcts in both
hemispheres. These venous infarcts are different from
arterial infarcts: cytotoxic edema is absent or mild,
vasogenic edema is prominent, and hemorrhagic
transformation or bleeding is usual. Despite this
hemorrhagic component heparin is the treatment of
choice.
Cerebral venous thrombosis can lead to a venous infarct.
Venous infarcts are different from arterial infarcts:
cytotoxic edema is absent or mild, vasogenic edema is
prominent, and hemorrhagic transformation or bleeding
is usual.
Cellular pathology of ischemic stroke
Acute occlusion of a major brain artery causes a
stereotyped sequel of cellular alterations which evolve
over a protracted period of time and which depend on
the topography, severity, and duration of ischemia
[39]. The most sensitive brain cells are neurons,
followed – in this order – by oligodendrocytes, astro-
cytes, and vascular cells. The most vulnerable brain
regions are hippocampal subfield CA1, neocortical
Section 1: Etiology, pathophysiology, and imaging
6
layers 3, 5, and 6, the outer segment of striate nucleus,
and the Purkinje and basket cell layers of cerebellar
cortex. If blood flow decreases below the threshold of
energy metabolism, the primary pathology is necrosis
of all cell elements, resulting in ischemic brain infarct.
If ischemia is not severe enough to cause primary
energy failure, or if it is of so short duration that
energy metabolism recovers after reperfusion, a
delayed type of cell death may evolve which exhibits
the morphological characteristics of necrosis, apop-
tosis, or a combination of both. In the following,
primary and delayed cell death will be described
separately.
Primary ischemic cell death
In the core of the territory of an occluded brain
artery the earliest sign of cellular injury is neuronal
swelling or shrinkage, the cytoplasm exhibiting
microvacuolation (MV) which ultrastructurally has
been associated with mitochondrial swelling [40].
These changes are potentially reversible if blood flow
is restored before mitochondrial membranes begin
to rupture. One to two hours after the onset of ische-
mia, neurons undergo irreversible necrotic alterations
(red neuron or ischemic cell change). In conven-
tional hematoxylin-eosin-stained brain sections such
neurons are characterized by intensively stained eosi-
nophilic cytoplasma, formation of triangular nuclear
pyknosis, and direct contact with swollen astrocytes
(Figure 1.3). Electron-microscopically mitochondria
exhibit flocculent densities which represent denatu-
rated mitochondrial proteins. Ischemic cell change
must be distinguished from artifactual dark neurons
which stain with all (acid or basic) dyes and are not
surrounded by swollen astrocytes [41].
Control
Necrotic changes
Dark neuron artifact
sham surgery
red neuron
1 day 3 days sham surgery
4 hours
ghost neuron
2 hours
Acute ischemic changes
shrinkageswelling
Light-microscopical characteristics of rat infarction Figure 1.3. Light-microscopical
evolution of neuronal changes after
experimental middle cerebral occlusion.
(Modifiedwith permission from Garcia
et al. [126].)
Chapter 1: Neuropathology and pathophysiology of stroke
7
With ongoing ischemia, neurons gradually loose
their stainability with hematoxylin, they become
mildly eosinophilic, and, after 2–4 days, transform
to ghost cells with hardly detectable pale outline.
Interestingly, neurons with ischemic cell change are
mainly located in the periphery and ghost cells in the
center of the ischemic territory, which suggests that
manifestation of ischemic cell change requires some
residual or restored blood flow whereas ghost cells
may evolve in the absence of flow [39].
Primary ischemic cell death induced by focal
ischemia is associated with reactive and secondary
changes. The most prominent alteration during the
initial 1–2 hours is perivascular and perineuronal
astrocytic swelling, after 4–6 hours the blood–brain
barrier breaks down, resulting in the formation of
vasogenic edema, after 1–2 days inflammatory cells
accumulate throughout the ischemic infarct, and
within 1.5–3 months cystic transformation of the
necrotic tissue occurs together with the development
of a peri-infarct astroglial scar (Figure 1.4)
Delayed neuronal death
The prototype of delayed cell death is the slowly
progressing injury of pyramidal neurons in the CA1
sector of the hippocampus after a brief episode of
global ischemia [42]. In focal ischemia delayed neur-
onal death may occur in the periphery of cortical
infarcts or in regions which have been reperfused
before ischemic energy failure becomes irreversible.
Cell death is also observed in distant brain regions,
notably in the substantia nigra and thalamus.
The morphological appearance of neurons during
the interval between ischemia and the manifestation
of delayed cell death exhibits a continuum that
ranges from necrosis to apoptosis with all possible
combinations of cytoplasmic and nuclear morph-
ology that are characteristic for the two types of cell
death [43]. In its pure form, necrosis combines
karyorrhexis with massive swelling of endoplasmic
reticulum and mitochondria, whereas in apoptosis
mitochondria remain intact and nuclear fragmenta-
tion with condensation of nuclear chromatin gives
way to the development of apoptotic bodies.
A frequently used histochemical method for the
visualization of apoptosis is terminal deoxyribonu-
cleotidyl transferase (TdT)-mediated dUTP-biotin
nick-end labeling (TUNEL assay), which detects
DNA strand breaks. However, as this method may
also stain necrotic neurons, a clear differentiation is
not possible [44].
A consistent ultrastructural finding in neurons
undergoing delayed cell death is disaggregation of
Figure 1.4. Transformation of acute
ischemic alterations into cystic infarct.
Note pronounced inflammatory reaction
prior to tissue cavitation. PMN ¼
polymorphonuclear leukocyte. (Modified
with permission from Petito [39].)
Section 1: Etiology, pathophysiology, and imaging
8
ribosomes, which reflects the inhibition of protein
synthesis at the initiation step of translation [45].
Light-microscopically, this change is equivalent to
tigrolysis, visible in Nissl-stained material. Disturb-
ances of protein synthesis and the associated endo-
plasmic reticulum (ER) stress are also responsible for
cytosolic protein aggregation and the formation of
stress granules [46]. In the hippocampus, stacks
of accumulated ER may become visible but in other
areas this is not a prominent finding.
Pathology of the neurovascular unit
The classical pathology of ischemic injury differenti-
ates between the sensitivity of the various cell types
of brain parenchyma with the neurons as the most
vulnerable elements. The molecular analysis of injury
evolution, however, suggests that ischemia initiates a
coordinated multi-compartmental response of brain
cells and vessels, also referred to as the neurovascular
unit [47]. This unit includes microvessels (endothelial
cells, basal lamina matrix, astrocytic endfeet, peri-
cytes, and circulating blood elements), the cell body
and main processes of astrocytes, the nearby neurons
together with their axons, and supporting cells,
notably microglia and oligodendrocytes. It provides
the framework for the bi-directional communication
between neuron and supplying microvessel. Under
physiological conditions, the most prominent func-
tion is the neurovascular coupling for maintaining
adequate supply of brain nutrients and clearance of
waste products. Pathophysiological disturbances of
microcirculation, conversely, provoke coincidental
microvessel–neuron responses, possibly mediated
by alterations in the matrix of the vascular and non-
vascular compartments of the ischemic territory.
Severe ischemia induces primary cell death due to
necrosis of all cell elements. Not so severe or short-term
ischemia induces delayed cell death with necrosis,
apoptosis, or a combination of both. The neurovascular
unit provides the conceptual framework for the
propagation of injury from microvessels to neurons.
Animal models of stroke
According to the Framingham study, 65% of strokes
that result from vascular occlusion present lesions in
the territory of the MCA, 2% in the anterior and 9%
in the posterior cerebral artery territories; the rest is
located in brainstem, cerebellum, in watershed, or
multiple regions. In experimental stroke research, this
situation is reflected by the preferential use of MCA
occlusion models.
Transorbital middle cerebral artery occlusion: this
model was introduced in the 1970s for the production
of stroke in monkeys [48] and later modified for use
in cats, dogs, rabbits, and even rats. The procedure is
technically demanding and requires microsurgical
skills. The advantage of this approach is the possibility
to expose the MCA at its origin from the internal
carotid artery without retracting parts of the brain.
Vascular occlusion can thus be performed without the
risk of brain trauma. On the other hand, removal
of the eyeball is invasive and may evoke functional
disturbances which should not be ignored. Surgery
may also cause generalized vasospasm which may
interfere with the collateral circulation and, hence,
induce variations in infarct size. The procedure there-
fore requires extensive training before reproducible
results can be expected.
The occlusion of the MCA at its origin interrupts
blood flow to the total vascular territory, including
the basal ganglia which are supplied by the lenticulo-
striate arteries. These MCA branches are end-arteries
which in contrast to the cortical branches do not form
collaterals with the adjacent vascular territories. As a
consequence, the basal ganglia are consistently part of
the infarct core whereas the cerebral cortex exhibits
a gradient of blood flow which decreases from the
peripheral towards the central parts of the vascular
territory. Depending on the steepness of this gradient,
a cortical core region with the lowest flow values
in the lower temporal cortex is surrounded by a
variably sized penumbra which may extend up to
the parasagittal cortex.
Transcranial occlusion of the middle cerebral
artery: post- or retro-orbital transcranial approaches
for MCA occlusion are mainly used in rats and mice
because in these species the main stem of the artery
appears on the cortical surface rather close to its
origin from the internal carotid artery [49]. In con-
trast to transorbital MCA occlusion, transcranial
models do not produce ischemic injury in the basal
ganglia because the lenticulostriate branches origin-
ate proximal to the occlusion site. Infarcts, therefore,
are mainly located in the temporo-parietal cortex with
a gradient of declining flow values from the periph-
eral to the central parts of the vascular territory.
Filament occlusion of the middle cerebral artery:
the presently most widely used procedure for MCA
Chapter 1: Neuropathologyand pathophysiology of stroke
9
occlusion in rats and mice is the intraluminal filament
occlusion technique, first described by Koizumi et al.
[50]. A nylon suture with an acryl-thickened tip is
inserted into the common carotid artery and ortho-
gradely advanced, until the tip is located at the origin
of the MCA. Modifications of the original technique
include different thread types for isolated or com-
bined vascular occlusion, adjustments of the tip size
to the weight of the animal, poly-L-lysine coating of
the tip to prevent incomplete MCA occlusion, or the
use of guide-sheaths to allow remote manipulation of
the thread for occlusion during polygraphic record-
ings or magnetic resonance imaging.
The placement of the suture at the origin of the
MCA obstructs blood supply to the total MCA sup-
plied territory, including the basal ganglia. It may also
reduce blood flow in the anterior and posterior cere-
bral arteries, particularly when the common carotid
artery is ligated to facilitate the insertion of the thread.
As this minimizes collateral blood supply from these
territories, infarcts are very large and produce massive
ischemic brain edema with a high mortality when
experiments last for more than a few hours. For this
reason, threads are frequently withdrawn 1–2 hours
following insertion. The resulting reperfusion sal-
vages the peripheral parts of the MCA territory, and
infarcts become smaller [51]. However, the pathophy-
siology of transient MCA occlusion differs basically
from that of the clinically more relevant permanent
occlusion models, and neither the mechanisms of
infarct evolution nor the pharmacological responsive-
ness of the resulting lesions replicate that of clinical
stroke [52].
Transient filament occlusion is also an inappro-
priate model for the investigation of spontaneous or
thrombolysis-induced reperfusion. Withdrawal of the
intraluminal thread induces instantaneous reperfu-
sion whereas spontaneous or thrombolysis-induced
recanalization results in slowly progressing recir-
culation. As post-ischemic recovery is greatly influ-
enced by the dynamics of reperfusion, outcome and
pharmacological responsiveness of transient filament
occlusion is distinct from most clinical situations of
reversible ischemia, where the onset of reperfusion is
much less abrupt.
Clot embolism of middle cerebral artery: MCA
embolism with autologous blood clots is a clinically
highly relevant but also inherently variable stroke
model which requires careful preparation and place-
ment of standardized clots to induce reproducible
brain infarcts [53]. The most reliable procedure for
clot preparation is thrombin-induced clotting of auto-
logous blood within calibrated tubings, which results
in cylindrical clots that can be dissected in segments
of equal length. Selection of either fibrin-rich (white)
or fibrin-poor (red) segments influences the speed
of spontaneous reperfusion and results in different
outcome. Clots can also be produced in situ by
microinjection of thrombin [54] or photochemically
by ultraviolet illumination of the MCA following
injection of rose Bengal [55].
The main application of clot embolism is for the
investigation of experimental thrombolysis. The drug
most widely used is human recombinant tissue plas-
minogen activator (rtPA) but the dose required in
animals is much higher than in humans, which must
be remembered when possible side-effects such as
rtPA toxicity are investigated. The hemodynamic
effect, in contrast, is similar despite the higher dose
and adequately reproduces the slowly progressing
recanalization observed under clinical conditions.
A recent development of clinical stroke treatment
and possibly the central challenge for future animal
research is interventional thrombectomy [56]. The
animal most widely used for this research is the swine
but as in this species the carotid access to the anterior
cerebral vasculature is impeded by a rete mirabile, clot
embolism and retrieval is carried out via the internal
maxillary or lingual artery [57]. Angiographic studies
confirm that clot retrieval using either aspiration or
removable stent devices results in immediate recana-
lization but a detailed pathophysiological analysis of
post-ischemic reperfusion is not yet available. It is,
therefore, premature to speculate whether this treat-
ment and its effect on post-ischemic recovery can also
be replicated in smaller animals by technically simpler
mechanical occlusion models, such as transient fila-
ment occlusion.
Various procedures for artery occlusion models, mostly
middle cerebral artery occlusion models, were developed
to study focal ischemia in animals.
Hemodynamics of stroke
Normal regulation of blood flow
In the intact brain, CBF is tightly coupled to the
metabolic requirements of tissue (metabolic regula-
tion) but the flow rate remains essentially constant
over a wide range of blood pressures (autoregulation).
Section 1: Etiology, pathophysiology, and imaging
10
An important requirement for metabolic regula-
tion is the responsiveness of blood vessels to carbon
dioxide (CO2 reactivity), which can be tested by the
application of carbonic anhydrase inhibitors or CO2
ventilation. Under physiological conditions, blood
flow doubles when CO2 rises by about 30 mmHg,
and is reduced by one-third when CO2 declines by
15 mmHg. The vascular response to CO2 depends
mainly on the changes of extracellular pH but it is
also modulated by other factors such as prostanoids,
NO, and neurogenic influences.
Autoregulation of CBF is the remarkable capacity
of the vascular system to adjust its resistance in such a
way that blood flow is kept constant over a wide range
of cerebral perfusion pressures (80–150 mmHg). The
range of autoregulation is shifted to the right, i.e. to
higher values, in patients with hypertension and to
the left during hypercarbia.
The mechanism of autoregulation is complex [58].
The dominating factor is a pressure-sensitive direct
myogenic response initiated by the activation of
stretch-sensitive cation channels of vascular smooth
muscle. In addition, a flow-sensitive indirect smooth
muscle response is initiated by changes in the shear
stress of endothelial cells, which result in activation of
various signal transduction pathways. Other influ-
ences are mediated by metabolic and neurogenic
factors but these may be secondary effects and are of
lesser significance.
Metabolic regulation: cerebral blood flow is coupled
to metabolic requirements of tissue by a vascular
response to changes in CO2. Autoregulation: cerebral
blood flow is kept constant over a wide range
of cerebral perfusion pressures.
Disturbances of flow regulation
Focal cerebral ischemia is associated with tissue acid-
osis which leads to vasoparalysis and, in consequence,
to a severe disturbance of the regulation of blood flow
[59]. In the center of the ischemic territory, CO2
reactivity is abolished or even reversed, i.e. blood flow
may decrease with increasing arterial pCO2. This
paradoxical “steal” effect has been attributed to the
rerouting of blood to adjacent non-ischemic brain
regions in which CO2 reactivity remains intact.
Stroke also impairs autoregulation but the dis-
turbance is more severe with decreasing rather than
with increasing blood pressure. This is explained by
the fact that in the ischemic tissue a decrease of local
brain perfusion pressure cannot be compensated by
further vasorelaxation whereas an increase may shift
the local perfusion pressure into the autoregulatory
range and cause vasoconstriction. An alternative
explanation is “false autoregulation” due to brain
edema which causes an increase in local tissue pres-
sure that precludes a rise of the actual tissue perfusion
pressure. Failure of cerebral autoregulation can be
demonstrated in such instances by dehydratingthe
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 oxygen require-
ments of the tissue, as reflected by the appearance of
red venous blood. With the cessation of tissue acido-
sis, vascular tone returns, and blood flow declines to
or below normal. At longer recirculation times auto-
regulation – but not CO2 reactivity – may recover,
resulting in persisting failure of metabolic regulation.
This is one of the reasons why primary post-ischemic
recovery may be followed by delayed post-ischemic
hypoxia and secondary metabolic failure [60].
Disturbances of flow regulation through ischemia:
tissue acidosis leads to vasorelaxation, CO2 reactivity is
abolished or even reversed, and autoregulation is
impaired.
Disturbances of microcirculation
With the increasing understanding of the pathobiol-
ogy of the neurovascular unit, microcirculatory
disturbances are recognized to contribute to the evo-
lution of ischemic brain injury [61]. Such disturb-
ances develop at the capillary level within the first
hour of focal ischemia and may persist even after full
reversal of vascular occlusion (incomplete microcir-
culatory reperfusion). The dominating pathology is
the narrowing of the capillary lumen, induced by
constriction of pericytes and swelling of pericapillary
astrocytic endfeet. The capillaries are filled with
aggregated red blood cells, leukocytes, and fibrin/
platelet deposits, the high viscosity of which adds to
the increased vascular resistance of the reduced
capillary lumen.
The mechanism of microcirculatory impairment
is multifactorial. Pericytes constrict in response to the
generation of reactive oxygen species (ROS), swelling
of astrocytic endfeet is due to cytotoxic brain edema,
and leukocyte adhesion to the vessel wall is part of the
Chapter 1: Neuropathology and pathophysiology of stroke
11
inflammatory response mediated by the generation of
chemoattractants, cytokines, and chemokines. Finally,
the activation of proteolytic enzymes contributes
to the dismantlement of basal lamina and results in
damage of the blood–brain barrier, an increase
in interstitial tissue pressure, and the risk of hemor-
rhagic transformation.
The impairment of microcirculation is equivalent
to a reduction of nutritional blood flow. During per-
manent vascular occlusion it aggravates the effect of
primary ischemia, particularly in the borderzone of
the infarct, and after transient vascular occlusion it
prevents adequate reoxygenation despite recanaliza-
tion of the supplying artery. It is still unresolved to
what extent microcirculatory impairment contributes
to or originates from ischemic injury but there is
general consent that microvascular protection is a
requirement for successful stroke treatment [62].
Focal brain ischemia is aggravated by microcirculatory
disturbances which may persist despite recanalization.
Anastomotic steal phenomena
The brain is protected against focal disturbances of
blood flow by the collateral circulation, which pro-
vides a subsidiary network of vascular channels when
principal conduits fail [63]. However, the connection
of ischemic and non-ischemic vascular territories by
anastomotic channels may divert blood from one
brain region to another, depending on the magnitude
and direction of the blood pressure gradients across
the anastomotic connections (for review see Tode and
McGraw [64]). The associated change of regional
blood flow is called “steal” if it results in a decrease in
flow, or “inverse steal” if it results in an improvement
in flow. Inverse steal has also been referred to as the
Robin Hood syndrome in analogy to the legendary
hero who took from the rich and gave to the poor.
Steals are not limited to a particular vascular ter-
ritory and may affect both the extra- and intracerebral
circulation. Examples of extracerebral steals are the
subclavian, the occipital-vertebral, and the ophthal-
mic steal syndrome. Intracerebral steal occurs across
collateral pathways of brain, notably the circle of
Willis and Heubner’s network of pial anastomoses.
The pathophysiological importance of steal has been
disputed but as it depends on the individual hemody-
namic situation it may explain unintended effects
when flow is manipulated by alterations of arterial
pCO2 or vasoactive drugs. Most authors, therefore, do
not recommend such manipulations for the treatment
of stroke.
“Steal”: decrease in focal blood flow when blood is
diverted from one brain region to another by
anastomotic channels; “inverse steal” if that results in an
improvement in flow.
The concept of ischemic penumbra
Energy requirements of brain tissue
The energy demand of the central nervous tissue is
very high and therefore sufficient blood supply to the
brain must be maintained constantly. A normal adult
male’s brain containing about 130 billion neurons
(21.5 billion in the neocortex) [65] comprises only
2% of total body mass, yet consumes at rest approxi-
mately 20% of the body’s total basal oxygen consump-
tion supplied by 16% of the cardiac blood output. The
brain’s oxygen consumption is almost entirely for the
oxidative metabolism of glucose, which in normal
physiological conditions is the almost exclusive sub-
strate for the brain’s energy metabolism (Table 1.1)
[66]. Glucose metabolized in neuronal cell bodies is
mainly to support cellular vegetative and house-
keeping functions, e.g. axonal transport, biosynthesis
of nucleic acids, proteins, and lipids, as well as other
energy-consuming processes not related directly to
the generation of action potentials. Therefore, the rate
of glucose consumption of neuronal cell bodies is
essentially unaffected by neuronal functional acti-
vation. Increases in glucose consumption (and
regional blood flow) evoked by functional activation
are confined to synapse-rich regions, i.e. the neuropil,
which contains axonal terminals, dendritic processes,
and also the astrocytic processes that envelop the
synapses. The magnitudes of these increases are lin-
early related to the frequency of action potentials in
Table 1.1. Cerebral blood flow (CBF), oxygen utilization
(CMRO2), and metabolic rates of glucose (CMRGIc) in man
(approximated values)
Cortex White
matter
Global
CBF (ml/100 g/min) 65 21 47
CMRO2
(μmol/100 g/min)
230 80 160
CMRGlc
(μmol/100 g/min)
40 20 32
Section 1: Etiology, pathophysiology, and imaging
12
the afferent pathways, and increases in the projection
zones occur regardless of whether the pathway is
excitatory or inhibitory. Energy requirements of func-
tional activation are due mostly to stimulation of the
Na+/K+-ATPase activity to restore the ionic gradients
across the cell membrane and the membrane poten-
tials following spike activity, and are rather high com-
pared to the basal energy demands of neuronal cell
bodies (Figure 1.5) [67].
In excitatory glutamatergic neurons, which
account for 80% of the neurons in the mammalian
cortex, glucose utilization during activation is medi-
ated by astrocytes which by anaerobic glycolysis pro-
vide lactate to the neurons where it is used for
oxidative metabolism [68]. Overall, 87% of the total
energy consumed is required for signaling, mainly
action potential propagation and postsynaptic ion
fluxes, and only 13% is expended in maintaining
membrane resting potential (Figure 1.5) [69].
The mechanisms by which neurotransmitters
other than glutamate influence blood flow and energy
metabolism in the brain are still not understood [70].
A normal adult male’s brain comprises only 2% of total
body mass, yet consumes at rest approximately 20% of
the body’s total basal oxygen consumption. Glucose is
the almost exclusivesubstrate for the brain’s energy
metabolism; 87% of the total energy consumed is
required for signaling, mainly action potential
propagation and postsynaptic ion fluxes.
Viability thresholds of brain ischemia
The different amounts of energy required for the
generation of membrane potential and the propaga-
tion of electrical activity are reflected by different
thresholds of oxygen consumption and blood
flow that must be maintained to preserve neuronal
function and morphological integrity. Flow values
below normal but above the threshold of neuronal
function are referred to as “benign oligemia.”
The flow range between the thresholds of neuronal
function and morphological integrity is called the
“ischemic penumbra” [71]. It is characterized by
the preservation of membrane polarization and the
potential of functional recovery without morpho-
logical damage, provided that local blood flow can
be re-established [72, 73]. The “infarct core” is the
area in which blood flow declines below the thresh-
old of morphological integrity and in which tissue
necrosis evolves.
According to the classical concept of viability
thresholds, functional activity – reflected by the
amplitudes of spontaneous and evoked electrical
activity – begins to decline at flow values below 50%
of control and is completely suppressed at about 30%
of control [71]. In awake monkeys these values cor-
respond to the progression of neurological injury
from mild paresis at 22 ml/100 g/min to complete
paralysis at 8 ml/100 g/min. Morphological damage
AstrocyteGlutamate-releasingpresynaptic terminal
Glycolysis
Glucose
Lactate
Glucose
Capillary
34% postsynaptic ion fluxes
3% glial resting potential
3% glutamate recycling
47% action potential propagation
3% presynaptic Ca2+
10% neuronal resting
potential
Glu
Glu
EAAT
Oxidative
phosphorylation
Gln
Gln
Postsynaptic site
(a) (b)
Na+/K+-ATPase
Na+
Na+
K+
NMDAR
lonotropic glutamate receptor
Figure 1.5. (a) Schematic representation of the mechanism for glutamate-induced glycolysis in astrocytes during physiological activation
[127]. (b). Distribution of energy expenditure in rat cortex at a mean spike rate of 4 Hz: most energy is required for activity, only 13% is
used for maintenance of resting potentials of neurons and glial cells [69,128]. EAAT ¼ excitatory amino-acid transporter; NMDAR ¼ N-methyl-
D-aspartate receptor.
Chapter 1: Neuropathology and pathophysiology of stroke
13
evolves as soon as cell membranes depolarize (“ter-
minal” depolarization) and occurs at flow values
below 15–20% of control. Biochemically, functional
suppression is associated with the inhibition of pro-
tein synthesis at about 50% and the development of
lactacidosis at 30–40% of control, whereas membrane
depolarization and morphological injury correspond
to the breakdown of energy metabolism and the loss
of adenosine triphosphate (ATP) at about 18% of
control (Figure 1.6).
A more detailed picture of the dynamics of injury
evolution is obtained by the simultaneous recording
of local blood flow and spontaneous unit activity of
cortical neurons [74]. According to these measure-
ments, unit activity disappeared at a mean value of
18 ml/100 g/min but the large variability of the func-
tional thresholds of individual neurons (6–22 ml/
100 g/min) indicates differential vulnerability even
within small cortical sectors. This explains the gradual
development of neurological deficits, which may be
related to differences in single cell activity with regu-
lar or irregular discharges at flow levels above the
threshold of membrane failure.
Whereas neuronal function is impaired immedi-
ately when flow drops below the threshold, the devel-
opment of irreversible morphological damage is time
dependent. Based on recordings from a considerable
number of neurons during and after ischemia of
varying degree and duration it was possible to con-
struct a discriminant curve representing the worst
possible constellation of residual blood flow and dur-
ation of ischemia still permitting neuronal recovery
(Figure 1.7). These results broaden the concept of the
ischemic penumbra: the tissue fate – potential of
recovery or irreversible damage – is determined not
only by the level of residual flow but also by the
duration of the flow disturbance. Each level of
decreased flow can, on average, be tolerated for a
defined period of time; flow between 17 and 20 ml/
100 g/min can be tolerated for prolonged but yet
undefined periods of time. As a rule used in many
experimental models, flow rates of 12 ml/100 g/min
lasting for 2–3 hours lead to large infarcts, but indi-
vidual cells may become necrotic after shorter periods
of time and at higher levels of residual flow.
The ischemic penumbra is the range of perfusion
between the flow threshold for preservation of function
and the flow threshold for preservation of morphological
integrity. It is characterized by the potential for
functional recovery without morphological damage.
Imaging of penumbra
Based on the threshold concept of brain ischemia, the
penumbra can be imaged on quantitative flow maps
using empirically established flow thresholds. A more
Figure 1.6. Diagrammatic
representation of viability thresholds
of focal brain ischemia.
EEG ¼ electroencephalogram; OEF ¼
oxygen extraction fraction; SEP ¼
somatosensory evoked potential.
Section 1: Etiology, pathophysiology, and imaging
14
Figure 1.7. (A) Activity of a single neuron during graded ischemia before, during, and after reversible MCA occlusion. (B) Recovery of neuronal
function after a limited period of ischemia. (C) Diagram of CBF thresholds required for the preservation of function and morphology of
brain tissue. The activity of individual neurons is blocked when flow decreases below a certain threshold (upper dashed line) and returns
when flow is raised again above this threshold. The fate of a single cell depends on the duration for which CBF is impaired below a certain level.
The solid line separates structurally damaged from functionally impaired, but morphologically intact tissue, the “penumbra.” The upper dashed
line distinguishes viable from functionally impaired tissue. EP ¼ evoked potentials. (Modified with permission from Heiss and Rosner [129]).
Chapter 1: Neuropathology and pathophysiology of stroke
15
precise approach is the imaging of threshold-
dependent biochemical disturbances to demarcate
the mismatch between disturbances which occur only
in the infarct core and others which also affect the
penumbra (Figure 1.8) [75]. Under experimental con-
ditions themost reliable way to localize the infarct core
is the loss of ATP on bioluminescent images of tissue
ATP content. A biochemical marker of core plus pen-
umbra is tissue acidosis or the inhibition of protein
synthesis. The penumbra is the difference between the
respective lesion areas. The reliability of this approach
is supported by the precise colocalization of gene tran-
scripts that are selectively expressed in the penumbra,
such as the stress protein hsp70, or the documentation
of the gradual disappearance of the penumbra with
increasing ischemia time [76].
Non-invasive imaging of the penumbra is possible
using positron emission tomography (PET) or mag-
netic resonance imaging (MRI). Widely used PET
parameters are the increase in oxygen extraction or
the mismatch between reduced blood flow and the
preservation of vitality markers, such as flumazenil
binding to central benzodiazepine receptors [77]. An
alternative PET approach is the use of hypoxia
markers such as 18F-misonidazole (F-MISO), which
is trapped in viable hypoxic but not in normoxic or
necrotic tissue [78].
The best-established MRI approach for penumbra
imaging is the calculation of mismatch maps between
the signal intensities of perfusion (PWI)and diffusion-
weighted images (DWI), but its reliability has been
questioned [79]. An alternative method is quanti-
tative mapping of the apparent diffusion coefficient
(ADC) of water, which reveals a robust correlation
with the biochemically characterized penumbra for
ADC values between 90% and 77% of control [80].
Recently MR stroke imaging has been performed by
combining PWI, DWI, and pH-weighted imaging
(pHWI) [81]. The mismatch between DWI and
pHWI detects the penumbra, and that between PWI
and pHWI the area of benign oligemia, i.e. a region in
which flow reduction is not severe enough to cause
metabolic disturbances. Diffusion kurtosis imaging
(DKI), an extension of diffusion imaging, demarcates
the regions with structural damage that cannot be
salvaged upon reperfusion [82].
Finally, new developments in MR molecular
imaging are of increasing interest for stroke research
[83]. These methods make use of contrast-enhanced
probes that trace gene transcription or of intracellular
conjugates that reflect the metabolic status and/or
bind to stroke markers. The number of molecules that
can be identified by these methods rapidly expands
and greatly facilitates the regional analysis of stroke
injury.
Non-invasive imaging of the penumbra is possible using
positron emission tomography (PET) or magnetic
resonance imaging (MRI).
Mechanisms of infarct expansion
With the advent of non-invasive imaging evidence has
been provided that brain infarcts grow (Figure 1.9).
This growth is not due to the progression of ischemia
because the activation of collateral blood supply and
spontaneous thrombolysis tend to improve blood
flow over time. Infarct progression can be differenti-
ated into three phases. During the acute phase tissue
Figure 1.8. Biochemical imaging of
infarct core, penumbra, and benign
oligemia after experimental middle
cerebral artery occlusion. The core is
identified by ATP depletion, the
penumbra by the mismatch between the
suppression of protein synthesis and ATP
depletion (top) or by the mismatch
between tissue acidosis and ATP
(bottom), and benign oligemia by the
reduction of blood flow in the absence of
biochemical alterations. (Modified
with permission from Hossman and
Mies [130]).
Section 1: Etiology, pathophysiology, and imaging
16
injury is the direct consequence of the ischemia-
induced energy failure and the resulting terminal
depolarization of cell membranes. At flow values
below the threshold of energy metabolism this injury
is established within a few minutes after the onset of
ischemia. During the subsequent subacute phase, the
infarct core expands into the peri-infarct penumbra
until, after 4–6 hours, core and penumbra merge. The
reasons for this expansion are peri-infarct spreading
depressions and a multitude of cell biological disturb-
ances, collectively referred to as molecular cell injury.
Moreover, a delayed phase of injury evolves which
may last for several days or even weeks. During this
phase secondary phenomena such as vasogenic
edema, inflammation, and possibly programmed cell
death may contribute to a further progression of
injury.
The largest increment of infarct volume occurs
during the subacute phase in which the infarct core
expands into the penumbra. Using multiparametric
imaging techniques for the differentiation between
core and penumbra, evidence could be provided that
in small rodents submitted to permanent occlusion of
the MCA at its origin, the penumbra equals the
volume of the infarct core at 1 hour, but after 3 hours
more than 50% and between 6 and 8 hours almost all
of the penumbra has disappeared and is now part of
the irreversibly damaged infarct core [76]. In larger
animals the infarct core may be heterogeneous with
multiple mini-cores surrounded by multiple mini-
penumbras but these lesions also expand and eventu-
ally progress to a homogeneous defect with a similar
time course [84].
Brain infarcts evolve in three phases:
� acute phase, within a few minutes after the onset of
ischemia; terminal depolarization of cell
membranes;
� subacute phase, within 4–6 hours; spreading
depression and molecular cell injury, the infarct core
expands into the peri-infarct penumbra;
� delayed phase, several days to weeks; vasogenic
edema, inflammation, and possibly programmed
cell death.
In the following, the most important mediators of
infarct progression will be discussed.
Peri-infarct spreading depression
A functional disturbance contributing to the growth
of the infarct core into the penumbra zone is the
generation of peri-infarct spreading depression-like
depolarizations (Figure 1.9) [85]. These depolariza-
tions are initiated at the border of the infarct core
and spread over the entire ipsilateral hemisphere.
During spreading depression the metabolic rate of
the tissue markedly increases in response to the
Figure 1.9. Relationship between peri-
infarct spreading depressions (above) and
infarct growth (below) during permanent
focal brain ischemia induced by occlusion
of the middle cerebral artery in rat. The
effect of spreading depressions on
electrical brain activity (EEG) and blood
flow (LDF) are monitored by DC recording
of the cortical steady potential, and infarct
growth by MR imaging of the apparent
diffusion coefficient (ADC) of brain water.
(Modified with permission from
Hossmann [131,132]).
Chapter 1: Neuropathology and pathophysiology of stroke
17
greatly enhanced energy demands of the activated ion
exchange pumps. In the healthy brain the associated
increase of glucose and oxygen demands are coupled
to a parallel increase of blood flow but in the peri-
infarct penumbra this flow response is suppressed or
even reversed [86]. As a result, a misrelationship
arises between the increased metabolic workload
and the low oxygen supply, leading to transient epi-
sodes of hypoxia and the stepwise increase in lactate
during the passage of each depolarization.
The pathogenic importance of peri-infarct depo-
larizations for the progression of ischemic injury is
supported by the linear relationship between the
number of depolarizations and infarct volume. Cor-
relation analysis of this relationship suggests that
during the initial 3 hours of vascular occlusion each
depolarization increases the infarct volume by more
than 20%. This is probably one of the reasons that
glutamate antagonists, which are potent inhibitors of
spreading depression, reduce the volume of brain
infarcts [87].
Peri-infarct spreading depressions are depolarizations
initiated at the border of the infarct core and may
contribute to progression of ischemic injury.
Molecular mechanisms of injury progression
In the borderzone of permanent focal ischemia or in
the core of the ischemic territory after transient vas-
cular occlusion, cellular disturbances may evolve that
cannot be explained by a lasting impairment of blood
flow or energy metabolism. These disturbances are
referred to as molecular injury, where the term
“molecular” does not anticipate any particular injury
pathway (for reviews see [88], [89]). The molecular
injury cascades (Figure 1.10) are interconnected in
complex ways, which makes it difficult to predict their
relative pathogenic importance in different ischemia
models. In particular, molecular injury induced by
transient focal ischemia is not equivalent to the alter-
ations that occur in the penumbra of permanent
ischemia. Therefore, the relative contribution of the
following injury mechanisms differs in different types
of ischemia.
Acidotoxicity: during ischemia oxygen depletion
and the associated activation of anaerobic glycolysis
cause an accumulation of lactic acid which, depending
on the severity of ischemia, blood glucose levels, and
the degree of ATP hydrolysis, results in a decline
of intracellular pH to between 6.5 and below 6.0.