Textbook of Stroke Medicine

464 Pages·2019·41.598 MB·English

by  Michael Brainin, Wolf-Dieter Heiss

Preface
This 3rd edition of our Textbook of Stroke Medicine con- Medicine” at the Danube University Krems in Austria,
tains mostly completely revised chapters and reflects a program that has been set up by the European Stroke
the tremendous advances in our field since the first Organisation and has been endorsed by the World
edition in 2010. It has been a fascinating challenge to Stroke Organization since 2007.
update and renew the contents without extending the We want to thank all contributors for their efforts
total length of the book. But following the develop- to update and supplement their chapters. We are very
ments in our field and the recommendations of many grateful that they have finished their tasks within an
colleagues, we added two new chapters: “Cerebral ambitious time plan in spite of many clinical and other
Small-Vessel Disease” and “Intensive Care of Stroke.” duties in their academic lives. Our thanks also go to
The chapter on endovascular interventions has been Susanne Tabernig, MD for providing excellent sum-
elongated due to recent trials offering new treatment maries for every chapter. We also thank our editors
options. Over time, this volume has served well the from Cambridge University Press, especially Emily
purpose and expectations of our younger colleagues Jones, who has been very patient with us and diligently
working in Stroke Medicine. Hopefully it will con- provided guidance and help.
tinue to do so. The book is focused on the “begin-
ning specialist,” many of whom have come from all Michael Brainin, MD
over the world to take the “Masters’ Degree in Stroke Wolf-Dieter Heiss, MD
ix
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Etiology, Pathophysiology, and Imaging
Section 1
Chapter Neuropathology and
1
Pathophysiology of Stroke
Konstantin-A. Hossmann and Wolf-Dieter Heiss
Neuropathology like CADASIL (cerebral autosomal dominant arte-
riopathy with subcortical infarcts and leukoencepha-
Vascular Origin of Cerebrovascular Disease lopathy), in some like cerebral amyloid angiopathy
a degenerative cause is discussed. All these vascular
In the latest edition of the International Classification
disorders can cause obstruction, and lead to throm-
of Diseases and Related Health Problems (ICD-1 1)
bosis and embolizations. Small vessels of the brain are
cere brovascular diseases (CVD) are listed in the section
affected by hyalinosis and fibrosis; this “small- vessel
of diseases of the nervous system [1]. However, they
disease” can cause lacunes and, if widespread, is the
have their origin in the vessels supplying or draining
substrate for vascular cognitive impairment and vas-
the brain, and the knowledge of pathological changes
cular dementia.
occurring in the vessels and in the blood are essential
Atherosclerosis is the most widespread disorder lead-
for understanding the pathophysiology and therapy
ing to death and serious morbidity including stroke [2].
of the various types of CVD. Changes in the vessel
The basic pathologic lesion is the atheromatous plaque,
wall lead to obstruction of blood flow; by interacting
the most commonly affected sites are the aorta, the cor-
with blood constituents they may cause thrombosis
onary arteries, the carotid artery at its bifurcation, and
and blockade of blood flow in this vessel. In addition
the basilar artery. Arteriosclerosis, a more generic term
to vascular stenosis or occlusion at the site of vascu-
describing hardening and thickening of the arteries,
lar changes, disruption of blood supply and consecu-
includes as additional types Mönkeberg’s sclerosis and
tive infarcts can also be produced by emboli arising
is characterized by calcification in the tunica media
from vascular lesions situated proximally to otherwise
and arteriolosclerosis with proliferative and hyaline
healthy branches located more distal in the arterial
changes affecting the arterioles. Atherosclerosis starts
tree or from a source located in the heart. At the site of
at young age, lesions accumulate and grow throughout
occlusion, opportunity exists for thrombus to develop
life and become symptomatic and clinically evident
in anterograde fashion throughout the length of the
when end organs are affected [3].
vessel, but this event seems to occur only rarely.
Atherosclerosis: atheromatous plaques, most commonly
Changes in large arteries supplying the brain,
in the aorta, the coronary arteries, the bifurcation of the
including the aorta, are mainly caused by atheroscle-
carotid artery and the basilar artery.
rosis. Middle-s ized and intracerebral arteries can also
be affected by acute or chronic vascular diseases of The initial lesion of atherosclerosis has been attrib-
inflammatory origin due to subacute to chronic infec- uted to “fatty streaks” and the “intimal cell mass.”
tions, e.g. tuberculosis and lues or due to collagen Those changes already occur in childhood and adoles-
disorders, e.g. giant cell arteritis, granulomatous angii- cence and do not necessarily correspond to the future
tis of the CNS, panarteritis nodosa, and even more sites of atherosclerotic plaques. Fatty streaks are focal
rarely systemic lupus erythematosus, Takayasu’s arte- areas of intra cellular lipid collection in both mac-
ritis, Wegener granulomatosis, rheumatoid arteritis, rophages and smooth muscle cells. Various concepts
Sjögren’s syndrome, Sneddon and Behçet’s disease. In have been proposed to explain the progression of such
some diseases affecting the vessels of the brain, the eti- precursor lesions to definite atherosclerosis [3, 4], most
ology and pathogenesis are still unclear, e.g. Moyamoya remarkable of which is the response-to-injury hypoth-
disease and fibromuscular dysplasia, but these dis- esis postulating a cellular and molecular response to
orders are characterized by typical locations of the various atherogenic stimuli in the form of an inflam- 1
vascular changes. Some arteriopathies are hereditary, matory repair process [5]. This inflammation develops
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Section 1: Etiology, Pathophysiology, and Imaging
concurrently with the accumulation of minimally oxi- grows. In vulnerable plaques thrombosis forming on
dized low density lipoproteins [6, 7], stimulates vas- the disrupted lesion further narrows the vessel lumen
cular smooth muscle cells (VSMCs), endothelial cells and can lead to occlusion or be the origin of emboli.
and macrophages [8], and as a result foam cells aggre- Less commonly, plaques have reduced collagen and
gate with an accumulation of oxidized LDL. In the elastin with a thin and weakened arterial wall, result-
further stages of artherosclerotic plaque development ing in aneurysm formation which when ruptured may
VSMCs migrate, proliferate, and synthesize extracellu- be the source of intracerebral hemorrhage (Figure 1.1).
lar matrix components on the luminal side of the ves- Injury hypothesis of progression to atherosclerosis: fatty
sel wall, forming the fibrous cap of the atherosclerotic streaks (focal areas of intra cellular lipid collection) →
lesion [9]. In this complex process of growth, progres- inflammatory repair process with stimulation of vascular
sion, and finally rupture of an atherosclerotic plaque, smooth muscle cells → atheromatous plaque.
a large number of matrix modulators, inflammatory Thromboembolism: Immediately after plaque rupture
mediators, growth factors, and vasoactive substances or erosion, subendothelial collagen, the lipid core, and
are involved. The complex interactions of these many procoagulants such as tissue factor and von Willebrand
factors are discussed in the special literature [6–10]. factor are exposed to circulating blood. Platelets rap-
The fibrous cap of the atherosclerotic lesion cov- idly adhere to the vessel wall through the platelet
ers the deep lipid core with a massive accumulation glycoproteins (GP) Ia/IIa and GP Ib/IX [12] with sub-
of extracellular lipids (atheromatous plaque), or fibro- sequent aggregation to this initial monolayer through
blasts and extracellular calcifications may contribute linkage with fibrinogen and the exposed GP IIb/IIIa
to a fibrocalcific lesion. Mediators from inflammatory on activated platelets. As platelets are a source of
cells at the thinnest portion of the cap surface of a nitrous oxide (NO), the resulting deficiency of bio-
vulnerable plaque – which is characterized by a larger active NO, which is an effective vasodilator, contrib-
lipid core and a thin fibrous cap – can lead to plaque utes to the progression of thrombosis by augmenting
disruption with formation of a thrombus or hema- platelet activation, enhancing VSMC proliferation
toma or even to total occlusion of the vessel. During and migration, and participating in neovasculariza-
the development of artherosclerosis the entire vessel tion [13]. The activated platelets also release adenosine
can enlarge or constrict in size [11]. However, once the diphosphate (ADP) and thromboxane A2 with subse-
plaque covers >40% of the vessel wall, the artery no quent activation of the clotting cascade. The growing
longer enlarges, and the lumen narrows as the plaque thrombus obstructs or even blocks the blood flow in
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
2 rupture (collagenases, elastases). (10) Thrombus formation.
(Modified from Faxon et al. 2004 [6].)
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Chapter 1: Neuropathology and Pathophysiology of Stroke
the vessel. Atherosclerotic thrombi are also the source by subarachnoid hemorrhage, 8.3% by intracerebral
for embolisms, which are the primary pathophysi- hemorrhage, and 1.2% by undefined diseases. In addi-
ologic mechanism of ischemic strokes, especially from tion, transient ischemic attacks accounted for 14.8%
carotid artery disease or of cardiac origin. of the total cerebrovascular events [22]. Since the
Rupture or erosion of atheromatous plaques → adhesion first Framingham reports, the rate of stroke death has
of platelets → thrombus → obstruction of blood flow and declined by more than one- third, but the relative fre-
source of emboli. quency distribution of completed stroke is essentially
the same [23].
Small-vessel disease usually affects the arterioles and
Ischemic strokes result from a critical reduction of
is associated with hypertension. It is caused by sub-
regional cerebral blood flow lasting beyond a critical
endothelial accumulation of a pathological protein,
duration, and are caused by atherothrombotic changes
the hyaline, formed from mucopolysaccharides and
of the arteries supplying the brain or by emboli from
matrix proteins. It leads to narrowing of the lumen or
sources in the heart, the aorta, or the large arteries. The
even occlusion of these small vessels. Often it is asso-
pathological substrate of ischemic stroke is ischemic
ciated with fibrosis, which affects not only arterioles,
infarction of brain tissue, the location, extension, and
but also other small vessels and capillaries and ven-
shape of which depend on the size of the occluded
ules. Lipohyalinosis also weakens the vessel wall pre-
vessel, the mechanism of arterial obstruction, and the
disposing for the formation of “miliary aneurysms.”
compensatory capacity of the vascular bed (Figure 1.2).
Small- vessel disease results in two pathological con-
Occlusion of arteries supplying defined brain territories
ditions: status lacunaris (lacunar state) and status
by atherothrombosis or embolizations lead to territo-
cribrosus (état criblé). Status lacunaris is character-
rial infarcts of variable size: they may be large – e.g. the
ized by small irregularly shaped infarcts due to occlu-
whole territory supplied by the middle cerebral artery –
sion of small vessels; it is the pathological substrate of
or small, if branches of large arteries are occluded or if
lacunar strokes and vascular cognitive impairment
compensatory collateral perfusion – e.g. via the circle of
and dementia. In status cribrosus small, round cavi-
Willis or leptomeningeal anastomoses – is efficient in
ties develop around affected arteries due to disturbed
reducing the area of critically reduced flow [15, 17]. In
supply of oxygen and metabolic substrate. These “cri-
a smaller number of cases, infarcts can also develop at
blures” together with miliary aneurysms are the sites of
the borderzones between vascular territories, when sev-
vessel rupture causing typical hypertonic intracerebral
eral large arteries are stenotic and the perfusion in these
hemorrhages [14–17]. A second type of small- vessel
“last meadows” cannot be constantly maintained above
disease is characterized by the progressive accumula-
the critical threshold of morphological integrity [24].
tion of congophilic, βA4 immuno-r eactive, amyloid
Borderzone infarctions are a subtype of the low- flow or
protein in the walls of small to medium- sized arteries
hemodynamically induced infarctions, which are the
and arterioles. Cerebral amyloid angiopathy is a patho-
result of critically reduced cerebral perfusion pres-
logical hallmark of Alzheimer’s disease and also occurs
sure in far- downstream brain arteries. The more com-
in rare genetically transmitted diseases, e.g. CADASIL
mon low- flow infarctions affect subcortical structures
and Fabry disease [18]. For a more detailed discussion
within a vascular bed with preserved but marginal
of the etiology and pathophysiology of the various spe-
irrigation [25]. Lacunar infarcts reflect disease of the
cific vascular disorders see [19–21].
vessels penetrating the brain to supply the capsule,
Small-vessel disease: subendothelial accumulation of
the basal ganglia, thalamus, and paramedian regions
hyaline in arterioles.
of the brainstem [26]. Most often they are caused by
lipohyalinosis of deep arteries (small-v essel disease),
Types of Cerebrovascular Disease
less frequent causes are stenosis of the MCA stem
Numbers relating to the frequency of the differ- and microembolization to penetrant arterial territo-
ent types of acute CVD are highly variable depend- ries. Pathologically these lacunes are defined as small
ing on the source of data. The most reliable numbers cystic trabeculated scars about 5 mm in diameter, but
come from the in- hospital assessment of stroke in the they are more often observed on magnetic resonance
Framingham study determining the frequency of com- images where they are accepted as lacunes up to 1.5 cm
pleted stroke: 60% were caused by atherothrombotic diameter. The classic lacunar syndromes include pure 3
brain infarction, 25.1% by cerebral embolism, 5.4% motor, pure sensory, and sensorimotor syndromes,
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Section 1: Etiology, Pathophysiology, and Imaging
Figure 1.2 Topography of the most common types of cerebral infarcts: (1) anterior cerebral artery (left: total infarction, right: infarct of
recurrent artery of Heubner); (2) anterior and middle cerebral arteries (left: with, right: without lenticulostriate arteries); (3) borderzone infarcts
between anterior and middle cerebral arteries; (4) cystic infarcts (left: centrum ovale, right: caudate); (5) and (6) middle cerebral artery (5
left: total, right: cortical, 6 left: minimal, right: wedge- shaped); (7) end- artery and borderzone infarcts of the perforating branches of middle
cerebral artery; (8) posterior cerebral artery (left: total, right: subtotal).
(With permission, Zülch 1985 [15].)
sometimes ataxic hemiparesis, clumsy hand, dysar- tissue consisting of neuronal ghosts and proliferating
thria, and hemichorea/hemiballism, but higher cer- astrocytes. However, the only significant difference
ebral functions are not involved. A new classification between “pale” and “red infarcts” is the intensity and
of stroke subtypes is mainly oriented on the most likely extension of the hemorrhagic component, since in at
cause of stroke: atherosclerosis, small- vessel disease, least two- thirds of all infarcts petechial hemorrhages
cardiac source, or other cause [27]. are microscopically detectable. Macroscopically, red
Territorial infarcts are caused by an occlusion of arteries infarcts contain multifocal bleedings which are more
supplying defined brain territories by atherothrombosis or less confluent and predominate in cerebral cortex
or embolizations. and basal ganglia which are richer in capillaries than
Borderzone infarcts develop at the borderzone the white matter [28]. If the hemorrhages become
between vascular territories and are the result of a confluent intrainfarct hematomas might develop, and
critically reduced cerebral perfusion pressure (low-flow extensive edema may contribute to mass effects and
infarctions). lead to malignant infarction. The frequency of hem-
Lacunar infarcts are mainly caused by small- vessel orrhagic infarctions (HIs) in anatomic studies ranged
disease. from 18% to 42% [29], with a high incidence (up to 85%
of HIs) in cardioembolic stroke [30].
Hemorrhagic infarctions, i.e. “red infarcts” in contrast
Mechanisms for hemorrhagic transformation
to the usual “pale infarcts,” are defined as ischemic
are manifold and vary with regard to the intensity of
infarcts in which varying amounts of blood cells are
bleeding. Petechial bleeding results from diapedesis
found within the necrotic tissue. The amount can range
rather than vascular rupture. In severe ischemic tis-
from a few petechial bleeds in the gray matter of cortex
sue vascular permeability is increased and endothelial
and basal ganglia to large hemorrhages involving the
tight junctions are ruptured. When blood circulation
cortical and deep hemispheric regions. Hemorrhagic
is spontaneously or therapeutically restored, blood can
transformation frequently appears during the sec-
leak out of these damaged vessels. This can also hap-
4 ond and third phases of infarct evolution, when mac-
pen with fragmentation and distal migration of an
rophages appear and new blood vessels are formed in
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Chapter 1: Neuropathology and Pathophysiology of Stroke
embolus (usually of cardiac origin) in the damaged These small vessel changes lead to weakening of the
vascular bed, explaining delayed clinical worsening vessel wall and miliary micro- aneurysm and consecu-
in some cases. For the hemorrhagic transformation tive small local bleedings, which might be followed by
also the collateral circulation might have an impact: secondary ruptures of the enlarging hematoma in a
in some instances reperfusion via pial networks may cascade or avalanche fashion [37]. After active bleed-
develop with the diminution of peri-i schemic edema at ing started it can continue for a number of hours with
borderzones of cortical infarcts. Risk of hemorrhage is enlargement of hematoma that is frequently associated
significantly increased in large infarcts with mass effect with clinical deterioration [38].
supporting the importance of edema for tissue damage Putaminal hemorrhages originate from a lateral
and the deleterious effect of late reperfusion. In some branch of the striate arteries at the posterior angle
instances also the rupture of the vascular wall second- resulting in an ovoid mass pushing the insular cortex
ary to ischemia-induced endothelial necrosis might laterally and displacing or involving the internal cap-
cause an intrainfarct hematoma. Vascular rupture sule. From this initial putaminal-c laustral location a
can explain very early hemorrhagic infarcts and early large hematoma may extend to the internal capsule and
intrainfarct hematoma (between 6 and 18 hours after lateral ventricle, into the corona radiata, and into the
stroke), whereas hemorrhagic transformation usually temporal white matter. Putaminal ICHs are considered
develops within 48 hours to 2 weeks. the typical hypertensive hemorrhages.
Hemorrhagic infarctions (HI) are defined as ischemic Caudate hemorrhage, a less common form of bleed-
infarcts in which varying amounts of blood cells are ing from distal branches of lateral striate arteries,
found within the necrotic tissue. They are caused by occurs in the head of the caudate nucleus. This bleed-
leakage from damaged vessels, due to increased vascular ing early connects to the ventricle and usually involves
permeability in ischemic tissue or vascular rupture the anterior limb of the internal capsule.
secondary to ischemia. Thalamic hemorrhages can involve most of this
Intracerebral hemorrhage (ICH) occurs as a result of nucleus and extend into the third ventricle medially
bleeding from an arterial source directly into the brain and the posterior limb of the internal capsule laterally.
parenchyma and accounts for 5–15% of all strokes The hematoma may press on or even extend into the
[31, 32]. Hypertension is the leading risk factor, but in midbrain. Larger hematomas often reach the corona
addition advanced age, race, and also cigarette smok- radiata and the parietal white matter.
ing, alcohol consumption, and high serum cholesterol Lobar (white matter) hemorrhages originate at the
levels have been identified. In a number of instances cortico- subcortical junction between gray and white
ICH occurs in the absence of hypertension usually in matter and spread along the fiber bundles most com-
atypical locations. These causes include small vascular monly in the parietal and occipital lobes. The hema-
malformations, vasculitis, brain tumors, and sympath- tomas are close to the cortical surface and usually not
omimetic drugs (e.g. cocaine). ICH may also be caused in direct contact with deep hemisphere structures or
by cerebral amyloid angiopathy and rarely is elicited by the ventricular system. As atypical ICHs they are not
acute changes in blood pressure, e.g. due to exposure to necessarily correlated with hypertension.
cold. The occurrence of ICH is also influenced by the Cerebellar hemorrhages usually originate in the area
increasing use of anti-t hrombotic and thrombolytic of the dentate nucleus from rupture of distal branches
treatment of ischemic diseases of the brain, heart, and of the superior cerebellar artery and extend into the
other organs [33, 34]. hemispheric white matter and into the fourth ventricle.
Spontaneous ICH occurs predominantly in the deep The pontine tegmentum is often compressed. A vari-
portions of the cerebral hemispheres (“typical ICH”) ant, the midline hematoma, originates from the cer-
[35]. Its most common location is the putamen (35–50% ebellar vermis, always communicates with the fourth
of cases). The subcortical white matter is the second most ventricle, and frequently extends bilaterally into the
frequent location (approximately 30%). Hemorrhages pontine tegmentum.
in the thalamus are found in 10–15%, in the pons in Pontine hemorrhages from bleeding of small para-
5–12%, and in the cerebellum in 7% of cases [36]. median basilar perforating branches cause medially
Most ICHs originate from the rupture of small, deep placed hematomas involving the basis of the pons.
arteries with diameters of 50–200 μm, which are A unilateral variety results from rupture of distal, 5
affected by lipohyalinosis due to chronic hypertension. long circumferential branches of the basilar artery.
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Section 1: Etiology, Pathophysiology, and Imaging
These hematomas usually communicate with the on, it is replaced by fibrous tissue, occasionally with
fourth ventricle, and extend laterally and ventrally into recanalization. The most common location of CVT is
the pons. the superior sagittal sinus and the tributary veins.
The frequency of recurrent ICHs in hypertensive Whereas some thromboses, particularly of the lat-
patients is rather low (6%) [39]. Recurrence rate is eral sinus, may have no pathological consequences for
higher with poor control of hypertension and also in the brain tissue, occlusion of large cerebral veins usu-
hemorrhages due to other causes. In some instances ally leads to a venous infarct. These infarcts are located
multiple simultaneous ICHs may occur, but also in in the cortex and adjacent white matter and often are
these cases the cause is another than hypertension. hemorrhagic. Thrombosis of the superior sagittal sinus
In ICHs, the local accumulation of blood destroys may lead only to brain edema, but usually causes bilat-
the parenchyma, displaces nervous structures, and eral hemorrhagic infarcts in both hemispheres. These
dissects the tissue. At the bleeding sites fibrin globes venous infarcts are different from arterial infarcts:
are formed around accumulated platelets. After hours cytotoxic edema is absent or mild, vasogenic edema is
or days extracellular edema develops at the periphery prominent, and hemorrhagic transformation or bleed-
of the hematoma. After 4–10 days the red blood cells ing is usual. Despite this hemorrhagic component hep-
begin to lyse, granulocytes and thereafter microglial arin is the treatment of choice.
cells arrive, and foamy macrophages are formed, which Cerebral venous thrombosis can lead to a venous infarct.
ingest debris and hemosiderin. Finally, the astrocytes Venous infarcts are different from arterial infarcts:
at the periphery of the hematoma proliferate and cytotoxic edema is absent or mild, vasogenic edema is
turn into gemistocytes with eosinophylic cytoplasma. prominent, and hemorrhagic transformation or bleeding
When the hematoma is removed, the astrocytes are is usual.
replaced by glial fibrils. After that period – extending
to months – the residue of the hematoma is a flat cav- Cellular Pathology of Ischemic Injury
ity with a reddish lining resulting from hemosiderin-
laden macrophages [36]. Acute interruption of cerebral blood flow causes a ste-
Intracerebral hemorrhage (ICH) occurs as a result of reotyped sequel of cellular alterations which evolve
bleeding from an arterial source directly into the brain over a protracted period of time and which depend
parenchyma, predominantly in the deep portions of the on the topography, severity, and duration of ischemia
cerebral hemispheres (typical ICH). Hypertension is [41]. Traditionally, these alterations have been studied
the leading risk factor, and the most common location by classical histological techniques, but recent develop-
is the putamen. ments in high resolution in vivo optical imaging such
Cerebral venous thrombosis can develop from many as multi-p hoton laser scanning microscopy (MPM),
causes and due to predisposing conditions. Cerebral optical coherence tomography (OCT), or photoacoustic
venous thrombosis (CVT) is often multifactorial, imaging (PAI) have opened the way to correlate mor-
when various risk factors and causes contribute to the phological alterations with functional disturbances [42].
development of this disorder [40]. The incidence of The most sensitive brain cells are neurons, followed –
septic CVT has been reduced to less than 10% of cases, in this order – by oligodendrocytes, astrocytes, and
but septic cavernous sinus thrombosis is still a severe, vascular cells. The most vulnerable brain regions are
however rare problem. Aseptic CVT occurs during hippocampal subfield CA, neocortical layers 3, 5,
1
puerperium and less frequently during pregnancy, and 6, the outer segment of striate nucleus, and the
but may also be related to use of oral contraceptives. Purkinje and basket cell layers of cerebellar cortex. If
Among the non-i nfectious causes of CVT congenital blood flow decreases below the threshold of energy
thrombophilia, particularly prothrombin and factor V metabolism, the primary pathology is necrosis of
Leiden gene mutations, as well as anti-t hrombin, pro- all cell elements, resulting in ischemic brain infarct.
tein C, and protein S deficiencies must be considered. If ischemia is not severe enough to cause primary
Other conditions with risk for CVT are malignancies, energy failure, or if it is of so short duration that
inflammatory diseases, and systemic lupus erythe- energy metabolism recovers after reperfusion, a
matosus. However, in 20–35% of CVT the etiology delayed type of cell injury may evolve which exhibits
6 remains unknown. The fresh venous thrombus is rich the morphological characteristics of necrosis, apop-
in red blood cells and fibrin and poor in platelets. Later tosis, necroptosis, or other forms of programmed cell
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Chapter 1: Neuropathology and Pathophysiology of Stroke
death [43]. In the following, primary and delayed cell represent denaturated mitochondrial proteins. Ischemic
death will be described separately. cell change must be distinguished from artifactual dark
neurons, which stain with all (acid or basic) dyes and are
Primary Neuronal Cell Death
not surrounded by swollen astrocytes [45].
In the core of the territory of an occluded brain artery With ongoing ischemia, neurons gradually lose
the earliest sign of cellular injury is neuronal swelling their stainability with hematoxilin, they become mildly
or shrinkage, the cytoplasm exhibiting microvacuola- eosinophilic, and, after 2–4 days, transform to ghost
tion (MV), which ultrastructurally has been associated cells with hardly detectable pale outline. Interestingly,
with mitochondrial swelling [44]. These changes are neurons with ischemic cell change are mainly located
potentially reversible if blood flow is restored before in the periphery and ghost cells in the center of the
mitochondrial membranes begin to rupture. One to ischemic territory, which suggests that manifesta-
two hours after the onset of ischemia, neurons undergo tion of ischemic cell change requires some residual or
irreversible necrotic alterations (red neuron or ischemic restored blood flow, whereas ghost cells may evolve in
cell change [ICC]). In conventional hematoxilin-e osin the absence of flow [41].
stained brain sections such neurons are characterized by Primary ischemic cell death induced by focal
intensively stained eosinophilic cytoplasma, formation ischemia is associated with reactive and secondary
of triangular nuclear pyknosis, and direct contact with changes. The most prominent alteration during the ini-
swollen astrocytes (Figure 1.3). Electron microscopi- tial 1–2 hours is perivascular and perineuronal astro-
cally mitochondria exhibit flocculent densities, which cytic swelling, after 4–6 hours the blood–brain barrier
Light-microscopical characteristics of rat infarction Figure 1.3 Light-microscopical evolu-
tion of neuronal changes after experi-
Acute ischemic changes
mental middle cerebral occlusion.
Control swelling shrinkage
(Modified with permission from Garcia
et al. 1995 [168].)
sham surgery 4 hours 2 hours
Necrotic changes
red neuron ghost neuron Dark neuron artifact
7
1 day 3 days sham surgery
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Section 1: Etiology, Pathophysiology, and Imaging
Figure 1.4 Transformation of acute
ischemic alterations into cystic infarct.
Note pronounced inflammatory
reaction prior to tissue cavitation.
(Modified with permission from Petito
2005 [41].)
breaks down resulting in the formation of vasogenic nuclear fragmentation with condensation of nuclear
edema, after 1–2 days inflammatory cells accumulate chromatin gives way to the development of apoptotic
throughout the ischemic infarct, and within 1.5–3 bodies. In hemorrhagic stroke lysed blood may induce
months cystic transformation of the necrotic tissue ferroptosis, a particular form of iron-d ependent cell
occurs together with the development of a peri-i nfarct death, which is characterized by lethal accumulation of
astroglial scar (Figure 1.4). lipid reactive oxygen species (ROS) [48].
A widely used histochemical method for the
Delayed Neuronal Death
visualization of apoptosis is terminal deoxyribonu-
The prototype of delayed cell death is the slowly pro- cleotidyl transferase (TdT)-mediated dUTP- biotin
gressing injury of pyramidal neurons in CA sector of nick- end labeling (TUNEL assay), which detects
1
hippocampus after a brief episode of global ischemia DNA strand breaks. However, as this method may
[46]. In focal ischemia delayed neuronal death may also stain necrotic neurons, a clear differentiation is
occur in the periphery of cortical infarcts or in regions not possible [49].
which have been reperfused before ischemic energy A consistent ultrastructural finding in neurons
failure becomes irreversible. Cell death is also observed undergoing delayed cell death is disaggregation of ribo-
in distant brain regions, notably in substantia nigra somes, which reflects the inhibition of protein synthesis
and thalamus. at the initiation step of translation [50]. Light micro-
The morphological appearance of neurons during scopically, this change is equivalent to tigrolysis, vis-
the interval between ischemia and the manifestation ible in Nissl-s tained material that corresponds to the
of delayed cell death exhibits a continuum that ranges dissociation of ribosomes from the rough endoplasmic
from necrosis to apoptosis with all possible combina- reticulum. Disturbances of protein synthesis and the
tions of cytoplasmic and nuclear morphology that are associated endoplasmic reticulum stress are also respon-
characteristic for the two types of cell death [47]. In its sible for cytosolic protein aggregation and the formation
pure form, necrosis combines karyorhexis with massive of stress granules [51]. In the hippocampus, stacks of
8 swelling of endoplasmic reticulum and mitochondria, accumulated endoplasmic reticulum may become vis-
whereas in apoptosis mitochondria remain intact and ible, but in other areas this is not a prominent finding.
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