Pathology Anatomy and Pathophysiology of Stroke

Chapter
Pathology, anatomy, and pathophysiology
2 of stroke
Louis R Caplan and David S Liebeskind
Introduction what the structures and diseases look like. For this reason, this
chapter relies heavily on illustrations.
Stroke is quite heterogeneous and not a single entity. Disorders
This chapter offers succinct and basic coverage of the topics
as different as rupture of a large blood vessel that causes flood-
just mentioned. We begin the chapter by introducing the
ing of the brain with blood and occlusion of a tiny artery with
various mechanisms of brain damage in stroke. These stroke
softening in a small but strategic brain site both qualify as
mechanisms are the major players, the key actors in the drama
strokes. These two pathological caricatures of stroke subtypes
of stroke. Their characterization, recognition, and treatment
are as divergent as grapes and watermelons, two very different
form the core of this book. Normal vascular anatomy and
substances that fit in the general category of fruit. Stroke refers
distribution are then described and illustrated. Next, the
to any damage to the brain or the spinal cord caused by an
usual distribution and frequency of these various mechanisms
abnormality of the blood supply. The term stroke is typically
in the blood vessels and in the brain are discussed and
used when the symptoms begin abruptly, whereas cerebrovas-
diagrammed. The chapter closes with a discussion of stroke
cular disease is a more general term that carries no connotation
pathophysiology, the dynamics of the functional response of
as to the tempo of brain injury. Of course, many patients with
the vascular system and brain to the primary injuries.
severely diseased blood vessels have no injury to brain tissue,
largely due to compensatory mechanisms such as collateral
circulation. A blood or cardiovascular abnormality precedes Pathology: mechanisms of cerebrovascular
and subsequently leads to the brain injury. Recognition of the
cardiac or cerebrovascular lesion or hematological disorder
damage to brain tissue
The first questions that the clinician should ask about a stroke
before the brain becomes damaged offers clinicians a window
patient are “What caused the brain dysfunction?” and “What
of opportunity during which brain damage can be prevented.
pathological process is active in this patient?” There are two
At times, even when brain injury has occurred, the patient
major categories of brain damage in stroke patients: (1) ische-
is unaware of any symptoms and neurologists may not be
mia, which is a lack of blood flow depriving brain tissue of
able to detect any abnormality on neurological examination.
needed fuel and oxygen; and (2) hemorrhage, which is the
Sophisticated neuroimaging techniques have taught clinicians
release of blood into the brain and into extravascular spaces
that such “silent strokes” are common, now posing an addi-
within the cranium or skull contents. Bleeding damages the
tional target for stroke prevention efforts
brain by cutting off connecting pathways and by causing loca-
Diagnosis and treatment of stroke patients require a basic
lized or generalized pressure injury to brain tissue; biochemical
understanding of the anatomy, physiology, and pathology of
substances released during and after hemorrhage also may
the major structures involved – the brain and spinal cord, the
adversely affect nearby vascular and brain tissues.1,2
heart and blood vessels that supply blood to these structures,
and the blood itself. To be effective, clinicians caring for stroke
patients must be intimately familiar with: (1) the appearance of Ischemia
the normal brain and its various lobes and regions; (2) the Ischemia can be further subdivided into three different
appearance of brain tissue damaged by various vascular dis- mechanisms: thrombosis, embolism, and decreased perfusion
orders; (3) the usual locations and course of arteries supplying or blood flow in a region of the brain. An analogy to a simple
the brain and spinal cord and veins that drain blood from these plumbing situation illustrates the differences among the
regions; and (4) the frequency, location, and appearance of mechanisms. Suppose that a homeowner calls a plumber and
diseases of the cerebrovascular system. Note that this discus- tells him that when the faucet in the second-floor bathroom at
sion includes a number of words related to vision. Many of the the right is turned on, water does not flow (Figure 2.1). The
diagnostic tests used, especially imaging of the brain and blood plumber finds that the pipe feeding the sink is rusty and has
vessels, produce pictures. Clinicians must be able to visualize become blocked. The plumber repairs the local pipe, and water
Caplan’s Stroke: A Clinical Approach, 5th Edition, ed. Louis R Caplan. Published by Cambridge University Press. © Cambridge
University Press, 2016.
Downloaded from https://www.cambridge.org/core. University College London (UCL), on 29 Apr 2018 at 10:01:14, subject to the Cambridge Core terms of use, available at
19
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781316095805.003
Part I: General principles
The most common type of vascular pathology is athero-

sclerosis, in which fibrous and muscular tissues overgrow in
the subintima, and fatty materials form plaques that can
encroach on the lumen. Next, platelets adhere to plaque
4
crevices and form clumps that serve as nidi for the deposition
of fibrin, thrombin, and clot.3,4 Figure 2.3 is a cartoon that
Sink
shows the development of plaque in a carotid artery in the
2nd floor neck with subsequent occlusion of the artery by thrombus
and embolization of the clot intracranially, causing a large
brain infarct in the distribution of that carotid artery.
Figure 2.4 is a photograph of a necropsy specimen that
3 shows a large thrombus in an internal carotid artery; the
1st floor lumen of the artery was nearly occluded by atherosclerotic
plaque. Atherosclerosis affects chiefly the larger extracranial
and intracranial arteries.5,6 Occasionally, a clot forms within
Tank
the lumen because of a primary hematological problem, such
Water Pump as polycythemia, thrombocytosis, or a systemic hypercoagul-
1 level able state. The smaller, penetrating intracranial arteries and
Basement 2
arterioles are more often damaged by hypertension than by
Figure 2.1 Cartoon of home plumbing illustrating possible problem areas: atherosclerotic processes.7,8 In such cases, increased arterial
(1) insufficient water in the tank; (2) low pump pressure; (3) low water pressure
in the pipes; and (4) rust build-up or blockage in a pipe leading directly to
tension leads to hypertrophy of the media and deposition of
the sink. fibrinoid material into the vessel wall, a process that gradually
encroaches on the already small lumen. Small atheromatous
deposits, often referred to as microatheromas, can obstruct
flow is restored. The local occlusive process in the pipe, in the orifices of penetrating arteries.
vascular terms, would qualify as thrombosis, meaning a process Less common vascular pathologies leading to obstruction
that occurs in situ within a blood vessel. Suppose instead that include: (1) fibromuscular dysplasia,9 an overgrowth of medial
the pipe had been blocked by material that originated in the and intimal elements that compromises vessel contractility
water tank and simply became lodged in the pipe to the sink, and luminal size; (2) arteritis, especially of the Takayasu10 or
occluding the pipe. This obstruction by material originating giant-cell type11; (3) dissection of the vessel wall,12 often with a
from afar is referred to as embolism. Fixing the local pipe would luminal or extraluminal clot temporarily obstructing the
not prevent additional material from getting into the system vessel; and (4) hemorrhage into a plaque,13 leading to acute
and blocking other pipes. Suppose instead that the plumber or chronic luminal compromise. At times, the focal vascular
finds that the water pressure is intermittently low and the flow abnormality is a functional change in the contractility of blood
to all the sinks and showers is deficient because of a leak in the vessels. Intense focal vasoconstriction can lead to decreased
water tank or low water pressure in the house’s entire plumb- blood flow and thrombosis. Dilatation of blood vessels also
ing system. This situation is akin to systemic hypoperfusion, alters local blood flow and clots often form in dilated
low blood flow; there is no local problem with the pipe to a segments.14
single sink but instead a general circulatory problem or factor
limiting the delivery of blood flow. Clearly, these three situa- Embolism
tions dictate different management by the plumber, and that is In embolism, material formed elsewhere within the vascular
the main reason for separating them into the three mechan- system lodges in an artery and blocks blood flow. Blockage can
isms. This analogy will also be referred to in Chapter 6 when be transient or may persist for hours or days before moving
treatment is discussed distally. In contrast to thrombosis, embolic luminal blockage is
not caused by a localized process originating within the
Thrombosis blocked artery. The material arises proximally, most com-
By convention, thrombosis refers to an obstruction of blood monly from the heart; from major arteries such as the aorta,
flow due to a localized occlusive process within one or more carotid, and vertebral arteries; and from systemic veins
blood vessels. Although this implies that thrombus or clot is (Figure 2.5). Cardiac sources of embolism include the heart
the cause of the blockage, such an obstruction can also be valves and clots or tumors within the atrial or ventricular
caused by atherosclerotic plaque with superimposed thrombo- cavities.15 Artery-to-artery emboli are composed of clots,
tic occlusion. The lumen of the vessel is narrowed or occluded platelet clumps, or fragments of plaques that break off from
by an alteration in the vessel wall or by superimposed clot the proximal or upstream vessels.16 Clots originating in sys-
formation. Figure 2.2A shows a normal artery, Figure 2.2B temic veins travel to the brain through venous to arterial
shows plaque encroaching on the arterial lumen, and shunts including cardiac defects such as an atrial septal defect
Figure 2.2C shows occlusion of the artery by a red thrombus or a patent foramen ovale, a process termed paradoxical
which has formed on top of a white platelet–fibrin thrombus. embolism.17 Also, occasionally air, fat, plaque material,
20
Chapter 2: Pathology, anatomy, and pathophysiology of stroke
Figure 2.2 (A) The drawing shows a normal

brain-supplying artery. The insert shows the various
layers within a normal artery. (B) Atherosclerotic
plaque within an artery narrowing the lumen. (C) White
Adventitia and red thrombi occluding a longitudinal segment of
an artery.
Artery
wall Media
(smooth muscle
and connective tissue)
Lumen Intima
(endothelium)
A Lumen
Plaque
White platelet-fibrin
thrombus
Figure 2.3 Internal carotid artery atherosclerotic lesions: (A) plaque;

(B) plaque with platelet–fibrin emboli; (C) plaque with occlusive
thrombus; (D) recent ischemic cerebral infarct due to embolization of
the internal carotid artery thrombus.
A B C D
21
b
a
Figure 2.5 Examples of potential sources of embolism: (a) cardiac mural

thrombus; (b) vegetations on heart valve; (c) aortic plaque (d) emboli from
carotid plaque. Label (e) shows infarcted cortex in area supplied by terminal
anterior cerebral artery due to embolism.
Figure 2.4 Carotid artery removed at necropsy. The internal carotid artery
origin is nearly occluded by an atherosclerotic plaque. A long thrombus
protrudes from the plaque and extends far rostrally within the arterial lumen.
A part of this thrombus had embolized intracranially to cause a fatal brain both A and C).19–21 Asymmetric effects can result from
infarct. Courtesy of Dr Pierre Amarenco.
pre-existing vascular lesions causing an uneven distribution
of hypoperfusion.
particulate matter from injected drugs, bacteria, foreign
bodies, and tumor cells enter the vascular system and embolize Venous occlusions and venous hypertension
to brain arteries.18 The three main components in embolism Although the veins are always involved in the regulation of
are: the donor source, the embolic material, and the recipient blood flow through a region of the brain, consideration of
artery. An embolic mechanism is often inferred from the stroke pathophysiology typically focuses on the arterial
pattern of ischemic brain injury on imaging studies and the delivery or interruption of blood flow to the brain. In a small
location and appearance of arterial occlusion on vascular fraction of patients with strokes, the veins are the main or
imaging, but proof of embolism requires demonstration of initiating site of pathophysiology. Venous hypertension may
material traversing the blood vessels from a proximal to down- cause both ischemia and hemorrhage due to backup or
stream location or from material found in the recipient artery impaired drainage of blood from an area of the brain.
that only could have arisen proximally. Venous patterns of injury are defined by the venous anatomy,
much as arterial territories are determined by arterial anatomy.
Decreased systemic perfusion Due to the complexity, redundancy, and extensive capacity of
In systemic hypoperfusion, diminished flow to brain tissue is venous collaterals to redistribute blood in the brain, venous
caused by low systemic perfusion pressure. The most com- patterns are often more difficult to recognize. In Figure 2.7, the
mon causes are cardiac pump failure (most often due to main damage is in the distribution of the vein of Labbé.
myocardial infarction or arrhythmia) and systemic hypoten- Knowing that the occlusive pattern is venous is important in
sion (due to blood loss or hypovolemia). In such cases, the choosing treatment. The mechanisms of venous hypertension
lack of perfusion is more generalized than in localized cause injury by first preventing drainage or engorging an area
thrombosis or embolism and affects the brain diffusely and of the brain, which typically leads to hemorrhage. If the mass
bilaterally. Poor perfusion is most critical in borderzone or effect from such engorgement and hemorrhage becomes exces-
so-called watershed regions at the periphery of the major sive, then ischemia is caused when the arterial inflow pressure
vascular supply territories (Figure 2.6, compare B with does not exceed the venous pressure. This sequence of events is
22
Figure 2.6 In heart (pump) failure and watershed infarction: (A)

normal pump and arterial circulation; (B) low pump pressure and
borderzone ischemia. Water goes to the center of hoses (arteries),
and stippled areas show poor flow. In contrast, with (C) “blocked
hose” and middle cerebral artery infarction, water flow is deficient
in the center of supply (stippled area).
Pump
Pump
B
Pump
C
markedly different than arterial ischemia where hemorrhage

occurs after ischemia is maximal.
Hemorrhage
Hemorrhage can be further subdivided into four subtypes:
subarachnoid; intracerebral; subdural; and epidural
Damage caused by ischemia (Figure 2.9). These subtypes have different causes, pose differ-
The three mechanisms of brain ischemia are illustrated in ent clinical problems, and have different management.
Figure 2.8. All may lead to temporary or permanent tissue
injury. Permanent injury is termed infarction. Capillaries or Subarachnoid hemorrhage
other vessels within the ischemic tissue may also be injured, In subarachnoid hemorrhage, blood leaks out of the vascu-
so that reperfusion can lead to leakage of blood into the lar bed onto the brain’s surface and is disseminated quickly
ischemic tissue, resulting in hemorrhagic infarction.22 The via the spinal fluid pathways into the spaces around the
extent of brain damage depends on the location and duration brain (see Figure 2.9, top left).23,24 Bleeding most often
of the poor perfusion and the ability of collateral vessels to originates from aneurysms or arteriovenous malforma-
perfuse the tissues at risk. The systemic blood pressure, blood tions, but bleeding diatheses or trauma can also cause sub-
volume, and blood viscosity also affect blood flow to the arachnoid bleeding. A ruptured aneurysm releases blood
ischemic areas. Brain and vascular injuries may lead to rapidly at systemic blood pressure, suddenly increasing
brain edema during the hours and days after stroke. In the intracranial pressure, whereas bleeding from other causes
chronic phase, glial scars form, and macrophages gradually is usually slower and at lower pressures. The blood within
ingest the necrotic tissue debris within the infarct, leading to the subarachnoid space often contains substances that pro-
shrinkage of the volume of the infarcted tissue or to forma- mote vasoconstriction of the basal arteries that are bathed
tion of a frank cavity. in cerebrospinal fluid.
23
Affected area
Thrombosis
Affected area
Recipient
site
Embolism
Donor
site
B Embolus
Affected areas
Figure 2.7 Axial FLAIR MRI revealing hemorrhagic infarction of the left
temporal and parietal lobes dues to occlusion of the vein of Labbé.
Intracerebral hemorrhage
The terms intracerebral and parenchymal hemorrhage describe
bleeding directly into the brain substance. It is important to
Systemic hypoperfusion
distinguish such primary hemorrhagic strokes from hemor- C
rhagic transformation, where bleeding occurs into an area
Figure 2.8 Illustrations of the three major causes of brain ischemia.
of brain tissue shortly after ischemic stroke due to disruption Thrombosis: (A) the insert shows a thrombus in an atherosclerotic artery leading
of the blood–brain barrier and/or reperfusion. The cause of to a brain infarct. Embolism: (B) a thrombus that originated in a donor source
primary intracerebral hemorrhage is most often hypertension, embolized to the recipient site (shown in the insert) causing an embolic brain
infarct, and (C) systemic hypoperfusion. Infarcts are in borderzone regions.
with leakage of blood from small intracerebral arterioles
damaged by the elevated blood pressure.25–29 Bleeding
diatheses, especially from the prescription of anticoagulants
or from trauma, drugs, vascular malformations, and vasculo- function as a prison, restricting and strangulating their
pathies (such as cerebral amyloid angiopathy), also cause enclosed contents and forcing herniation of tissue from one
bleeding into the brain. Intracerebral hemorrhages occur in a compartment to another.30–32
localized region of the brain (see Figure 2.9, top right). The
degree of damage depends on the location, rapidity, volume, Subdural and epidural hemorrhages
and pressure of the bleeding. These hemorrhages are typically caused by head trauma.
Intracerebral hemorrhages are at first soft and dissect along Subdural hemorrhages arise from injured or torn bridging
white matter fiber tracts. When bleeding dissects into the veins that are located between the dura mater and the ara-
ventricles or onto the surface of the brain, blood is introduced chnoid membranes. The bleeding is most often slow and accu-
into the cerebrospinal fluid. The blood in the hematoma clots mulates during days, weeks, and even a few months. When a
and solidifies, causing swelling of adjacent brain tissues. Later, large vein is lacerated, bleeding can develop more rapidly over
blood is absorbed, and after macrophages clear the debris, hours to days. Epidural hemorrhages are caused by tearing of
a cavity or slit forms that may disconnect brain pathways meningeal arteries, most often the middle meningeal artery.
(Figure 2.10). The intracranial cavity is a closed system. The Blood accumulates rapidly over minutes to hours between the
bony skull and dura mater act as a fortress protecting the brain skull and the dura mater. Both subdural and epidural hemor-
from outside injury. In adverse situations, such as swelling or rhages cause symptoms and signs by compressing brain tissue
hemorrhage arising inside the fortress, these structures can and increasing intracranial pressure (see Figure 2.9, bottom).
24
Subarachnoid Aneurysm
hemorrhage
Figure 2.10 Brain specimen showing a slit-like cavity adjacent to the lateral
ventricle. A large putaminal hematoma had been present at this site. There is
Epidural Subdural also a butterfly-shaped infarct adjacent to the IIIrd ventricle that resulted from
hemorrhage hemorrhage herniation caused by the mass effect of the putaminal hemorrhage. The patient
survived for some time after the hemorrhage.
also affects treatment: Embolism arising from the heart

requires different therapeutic strategies than embolism arising
from localized vessel plaques. In regard to systemic hypoperfu-
sion, pump failure or hypovolemia owing to intestinal bleeding
needs urgent attention, which would be needlessly delayed by
inappropriate angiography or a futile search for a localized
extracranial vascular lesion.
In subarachnoid hemorrhage, the major aim of treatment is
to prevent the next aneurysmal leak, whereas in intracerebral
hemorrhage, rebleeding is rare and treatment is aimed at con-
trolling and limiting the bleeding and pressure effects of the
hemorrhage. When subdural and epidural hemorrhages are
Figure 2.9 Illustrations of the main types of brain hemorrhages:
intracerebral; subarachnoid; subdural; and epidural. sizable, surgical drainage is the main treatment.
To treat the stroke patient optimally, it is imperative that
the physician identify the correct mechanism of stroke.
Recognition of the stroke mechanism Because it is not always possible to be absolutely certain of
the single true mechanism, the clinician often must consider
guides treatment the possibility of more than one mechanism, such as throm-
The problems in these five major subtypes of stroke – thrombosis and embolism, and must evaluate for each. At times,
bosis, embolism, decreased systemic perfusion, subarachnoid more than one mechanism is operant. For example, in sub-
hemorrhage, and intracerebral hemorrhage – are quite distinct arachnoid hemorrhage, the blood may cause spasm of blood
and require different treatment strategies. Identifying the etiol- vessels and thus induce local ischemia, and a thrombus
ogy and underlying stroke mechanism is essential to guide obstructing a carotid artery can also fragment and lead to distal
rational therapy, both in the early or acute stage and to prevent artery-to-artery embolism. Furthermore, local hypoperfusion
recurrence. Some therapies suitable for ischemia would be and embolic events often coexist.
disastrous if the problem were hemorrhage (e.g., using anti-
coagulants or opening a blood vessel to diminish supposed
ischemia would augment hemorrhage). Even within the var-
Anatomy: common anatomical sites
ious subcategories of ischemia, treatment depends on the sub- of vascular and brain lesions
type or specific cause. For example, in a patient with embolism Clinical neurology differs from most medical specialties in its
arising from the heart, operating on a recipient artery for emphasis on, and even obsession with, the complex and unique
supposed local thrombosis would certainly be ineffective in anatomy of the cerebral circulation. To localize and repair
preventing subsequent embolism. The origin of an embolus damage to water pipes, the effective plumber must be aware
25
of exactly where the pipes are, what they supply, and where proximal supraclinoid portions. The termination of the intra-
they are most likely to be damaged by various hazards. cranial ICAs (the so-called T-portion because of its shape) is
Abnormal neurological signs and symptoms depend more on the bifurcation into the anterior cerebral arteries (ACAs),
the localization of the brain injury than on its mechanism. which course medially, and the middle cerebral arteries
Although all portions of the lung or liver look and function (MCAs), which course laterally. Figure 2.12 shows the major
identically, different regions within the brain appear and act intracranial branches of the ICA.
differently. The nervous system is a world of uncountable The ECAs have two major vascular channels that ordinarily
individual nerve cells and networks, each with quite different supply the face that can act as collateral circulation if the ICAs
and unique characteristics and chemical messengers. Each of occlude: the facial arteries, which course along the cheek toward
the various mechanisms of stroke just reviewed has its own the nasal bridge, where they are termed the angular arteries, and
preferences for anatomical brain locations. Identification of the preauricular arteries, which terminate as the superficial
the location of the stroke depends on analysis of the abnormal temporal arteries. The internal maxillary artery and ascending
neurological symptoms and signs and on interpretation of pharyngeal branches of the ECAs also can contribute to collat-
brain imaging. A major important question in every stroke eral circulation when an ICA occludes. The internal maxillary
patient is – where is the brain and vascular problem located? arteries give off the middle meningeal artery branches, which
Even once a specific region of the brain is implicated, questions penetrate into the skull through the foramen spinosum. Another
remain regarding the specific arterial or venous distribution important arterial supply of the face involves the frontal and
and the role of compensating collateral vessels that modify supratrochlear branches that originate from the ophthalmic
potential injury. arteries (ICA system), which supply the medial forehead above
This section reviews the important anatomical facts about the brow. When an ICA occludes, these ECA branches can be an
the extracranial and intracranial vessels,33 their normal or important source of collateral blood supply.
typical regions of supply or drainage, and the most common The ACAs course medially until they reach the longitudinal
locations for various vascular pathologies. Differences in the fissures and then run posteriorly over the corpus callosum.
anatomy of extracranial and intracranial arteries are outlined. They supply the anterior medial portions of the cerebral hemi-
Next, the anatomical predilections of the major stroke spheres and give off deep branches to the caudate nuclei and
mechanisms within the brain are discussed. Aspects of the the basal frontal lobes. Figure 2.13 shows the small artery
anatomy and localization of various lesions are reviewed branches of the ACAs. The first portion of the ACA is some-
more extensively in the second part of this book, where specific times hypoplastic on one side, in which case the ACA from the
stroke syndromes are addressed. Much as there is anatomical other side supplies both medial frontal lobes. The anterior
variation in the normal vascular anatomy of the brain, there are communicating artery connects the right and left ACAs and
many collateral flow patterns arising from neighboring vessels provides a means of collateral circulation from the anterior
that may be encountered with different stroke syndromes. circulation of the opposite side when one ACA is hypoplastic
or occludes.
Normal vascular anatomy The main stem of the MCAs course laterally, giving off
lenticulostriate artery branches to the basal ganglia and inter-
Arterial circulation nal capsule (Figure 2.14). Although most often the lenticu-
The common carotid arteries (CCAs) bifurcate in the neck, lostriate penetrating branches arise from the mainstem MCA,
usually opposite the upper border of the thyroid cartilage, into when the mainstem is short, the lenticulostriate branches may
the internal carotid arteries (ICAs), which are located poster- arise from the superior division branch. Similarly, lenticu-
iorly as a direct extension of the CCA, and into the external lostriate perforators may also arise from the terminal ICA or
carotid arteries (ECAs), which course more anteriorly and proximal ACA. As they near the sylvian fissures, the MCAs
laterally. The ICAs travel behind the pharynx; they give off usually trifurcate into an early anterior temporal branch that
no branches in the neck. Figure 2.11A shows the carotid courses inferiorly and then relatively larger superior and infer-
arteries in the neck. Figure 2.11B shows the branches of the ior divisions that arise from the most distal portion of the
ECA, which supplies the face and major cranial structures horizontal segment of the MCA as it reaches the sylvian fissure
except for the brain. The ICAs then enter the skull through near the insula. There is marked variability in such branching
the carotid canal within the petrous bone and form an patterns and angiographic descriptions have either utilized
S-shaped curve. The ICA within this curve is usually referred branch points as landmarks to distinguish various segments
to as the carotid siphon. There are three divisions of the ICA of the MCA or alternatively, named MCA segments based on
within the siphon – an intrapetrous portion, an intracavernous the location of adjacent brain regions. The superior division
portion within the cavernous sinus, and a supraclinoidal supplies the lateral portions of the cerebral hemispheres above
portion34 (Figure 2.11C). The siphon portion of the ICAs the sylvian fissures, and the inferior division supplies the
(usually the clinoidal segment but occasionally the intracaver- temporal and inferior parietal lobes below the sylvian fissures.
nous segment) gives rise to ophthalmic artery branches that Figure 2.15 is a view of the lateral surface of the left cerebral
exit anteriorly. The ICAs then penetrate the dura mater and hemisphere showing the MCA branches and the supply of the
give rise to anterior choroidal and posterior communicating superior and inferior divisions of the left MCA. Figure 2.16 is a
arteries, which arise and course posteriorly from their drawing of the paramedian sagittal surface of the cerebral
26
Figure 2.11 Drawings of the

major right-sided neck arteries.
(A) The innominate artery gives
rise to subclavian and CCA
branches. The right vertebral
artery is shown originating from
the right subclavian artery.
The common carotid artery
bifurcation into internal and
external carotid arteries is also
Internal maxillary artery shown. The external carotid
artery and its branches (B), and
(C) the segments of the ICA
are shown in relation to their
Occipital artery relationships with the adjacent
External carotid artery skull structures. ACA, anterior
Internal carotid cerebral artery; AChA, anterior
artery choroidal artery; CCA,
Facial artery common carotid artery; ECA,
Vertebral artery external carotid artery; ICA,
internal carotid artery; MCA,
Deep cervical middle cerebral artery; OA,
artery occipital artery; P.CommA,
posterior communicating artery.
Common carotid artery
Thyrocervical trunk
Subclavian artery Innominate artery
MCA ACA
Supraclinoid AChA
Superficial temporal segment
P. CommA OA
Internal maxillary Cavernous
segment
Posterior auricular Petrous
ECA
segment
Facial
Occipital
ICA Lingual
Ascending pharyngeal Cervical

segment ICA
Superior thyroid
CCA
ECA
B C
hemispheres showing the distribution of the ACA and poster- communicating arteries project posteriorly from the ICA.
ior cerebral artery (PCA) branches. The AChAs course posteriorly and laterally running along
The anterior choroidal arteries (AChAs) are relatively small the optic tract. They straddle territory between components
arteries that originate from the ICAs after the origins of the of the anterior (internal carotid) and posterior circulations
ophthalmic and posterior communicating arteries. The (vertebrobasilar system).35 The AChAs give off penetrating
ophthalmic artery projects anteriorly into the back of the artery branches to the globus pallidus and posterior limb of
orbit, whereas the anterior choroidal and posterior the internal capsule. They then give branches laterally to the
27
A-P view Figure 2.12 The intracranial

branches of the ICA. Anteroposterior
(A-P) view (A) and lateral view (B).
Pericallosal artery
Anterior cerebral artery
Recurrent artery of Heubner

Anterior choroidal artery
Middle cerebral artery
Ophthalmic artery
Internal carotid artery
Lateral view
Pericallosal artery
Ophthalmic artery
Posterior cerebral artery
B Anterior choroidal artery
medial temporal lobe, and medial branches supply a portion of By convention, the carotid artery territories just described
the midbrain and the thalamus. The AChAs end in the lateral are referred to as the anterior circulation (front of the brain),
geniculate body where they anastamose with lateral posterior whereas the vertebral and basilar arteries and their branches
choroidal artery branches of the PCAs and in the choroid are termed the posterior circulation (because they supply the
plexus of the lateral ventricles near the temporal horns. The back of the brain). Each ICA supplies roughly two-fifths of the
AChAs have a characteristic shape because of this meandering brain by volume, whereas the posterior circulation accounts
trajectory that crosses from medial to lateral, inferior to super- for approximately one-fifth of the total. Despite its much
ior, and anterior to posterior reaches. Figure 2.17 is a drawing smaller size, the posterior circulation contains the brainstem,
of the course of the AChA. Figure 2.18 shows a drawing of a a midline strategically critical structure without which con-
coronal section of the cerebral hemispheres showing the dis- sciousness, movement, and sensations cannot be preserved.
tribution of the supply of the MCA, ACA, PCA, and the AChA. The posterior circulation is constructed quite differently
More detailed maps of the distribution of the blood supply in from the anterior circulation and consists of vessels from
the cerebral hemispheres have been published.36 each side (the vertebral and anterior spinal artery branches),
28
Lateral lenticulostriate arteries

Medial lenticulostriate arteries

Recurrent artery (of Heubner)
Anterior communicating artery
Figure 2.13 Coronal post-mortem angiogram showing the branches of the Figure 2.14 Drawing of a coronal section of the cerebral hemispheres
anterior cerebral arteries (ACAs) (white arrows). The black dot region (left of showing one mainstem middle cerebral artery and its lenticulostriate artery
drawing) indicates the internal borderzone region. From Pullicino P, branches.
Lenticulostriate arteries. In Bogousslavsky J, Caplan LR (eds). Stroke Syndromes,
2nd ed. Cambridge: Cambridge University Press, 2001, pp 428–437.
Pericallosal artery
Posterior cerebral artery Anterior cerebral artery

A
Figure 2.16 Drawing of sagittal-section paramedian view of cerebral
hemispheres showing branches of the anterior (ACA) and posterior (PCA)
cerebral arteries.
which unite to form midline arteries that supply the brainstem

and spinal cord. Within the posterior circulation, there is a
much higher incidence of asymmetric, hypoplastic arteries; of
variability of supply; and of retention of fetal circulatory
patterns.37,38 This occurs due to incomplete fusion of two
lateral opposed vascular conduits to form the single posterior
circulation later in development. The proximal portions of the
posterior circulation on the two sides differ. On the right, the
subclavian artery arises from the innominate artery, a common
channel supplying the anterior and posterior circulations. On
the left side, the subclavian artery usually arises directly from
B
the aortic arch after the origin of the left CCA.
Figure 2.15 (A) Drawing of the lateral surface of the left cerebral hemisphere The first branch of each subclavian artery is the vertebral
showing the usual branches of the middle cerebral artery (MCA). (B) The
superior division MCA supply is mainly suprasylvian (pink) and the inferior artery (VA) (Figure 2.19; see also Figure 2.11). The VAs course
division mainly infrasylvian supply is shown in darker pink. upward and backward until they enter the transverse foramens
29
Figure 2.17 Drawing of

vascular supply territory of the
Optic nerve anterior choroidal artery
(AChA).
Temporal lobe
Posterior communicating artery
(cisternal segment)
Uncus
Basilar artery
Cerebral peduncle
(plexal segment)
Choroid fissure
Lateral geniculate body
Pineal
Choroidal branches from posterior

cerebral artery
ACA
V4
MCA V3
e
b
V2
c
d
a
AChA
V1
PCA
Figure 2.18 Drawing of a coronal view of the cerebral hemispheres showing

the vascular supply territories: The right side depicts territories supplied by the
anterior cerebral artery (ACA), middle cerebral artery (MCA), posterior cerebral
artery (PCA), and anterior choroidal artery (AChA). The left side depicts individual
vessels: (a) basilar artery; (b) thalamoperforators, which originate in the PCA; (c)
AChA; (d) MCA; (e) lenticulostriate arteries.
of the sixth or fifth cervical vertebra and run within the intra-
vertebral foramina, exiting to course behind the atlas before
piercing the dura mater to enter the foramen magnum. Their Figure 2.19 Drawing showing portions of the vertebral artery (VA) and their
relation to the bony vertebral column.
intracranial portions end at the medullopontine junction,
where the two VAs join to form the basilar artery. after exit from the vertebral column that arches behind the
Figure 2.19 shows the divisions of the VAs: the first portion atlas and before entry into the cranium (V3), and the intracra-
before entry into the bony vertebral column (V1), the portion nial portion (V4). In the neck, the VAs have many small
within the vertebral columns (V2), the portion of the artery muscular and spinal branches.
30
Anterior communicating Figure 2.20 Drawing of a basal view of the brain

artery showing the intracranial branches of the vertebral and
basilar arteries and the basal branches of the circle of
Willis and the carotid arteries.
Posterior communicating
artery
Superior cerebellar artery

Basilar artery
Anterior inferior
cerebellar artery
Posterior inferior
cerebellar artery
Vertebral artery
The intracranial portions of the VAs give off posterior

and anterior spinal artery branches, penetrating arteries to
Composition of cervico-cranial artery walls
The walls of the extracranial arteries consist of three well
the medulla and the large posterior inferior cerebellar
developed layers; intima, media, and adventitia45,46 (see
arteries (PICAs). The basilar artery runs in the midline
Figure 2.2A). The intima is composed of a single row of
along the clivus, giving off bilateral anterior inferior
endothelial cells that forms a continuous barrier between the
cerebellar artery (AICA) and superior cerebellar artery
arterial wall and the circulating blood. The endothelium sits on
(SCA) branches before dividing at the pontomesencephalic
a basal membrane that is separated from the internal elastic
junction into terminal PCA branches (Figure 2.20). The
lamina and the media by a space that contains an acellular
major arterial branches of the intracranial vertebral and
matrix containing collagen, elastin, and glycoproteins. The
basilar arteries as they appear on angiograms are shown on
internal elastic lamina is a thick fenestrated layer of elastin
Figure 2.21.
that separates the intima from the media. The media is the
The vascular supply of the brainstem has been worked
thickest component of the arterial wall and is composed of
out by Foix,39–41 Stopford,42 Gillilan,43 and Duvernoy44
smooth muscle, elastic fibers, and an extracellular matrix. The
and is illustrated in Figure 2.22. Large paramedian arteries
external elastic lamina separates the media and adventitia. The
and smaller, short circumferential arteries penetrate
outermost layer of the arterial wall, the adventitia, is composed
through the basal portions of the brainstem into the
of loose connective tissue and adipose cells. Nerves and vessels
tegmentum. Long circumferential arteries course around
(so-called vasa vasorum) penetrate the adventitia and may
the brainstem giving off branches to the lateral tegmen-
extend into the media.
tum. The PCAs give off penetrating arteries to the
Intracranial arteries are morphologically different from
midbrain and thalamus, course around the cerebral
extracranial arteries. Intracranial arteries have no external
peduncles, and then supply the occipital lobes and inferior
elastic membrane and have a thinner intimal layer. The
surface of the temporal lobes (Figure 2.23). The circle of
media and adventitia are relatively poor in elastic fibers when
Willis allows for connections between the anterior circula-
compared to extracranial arteries of comparable size.45,46
tions of each side, through the anterior communicating
artery, and between the posterior and anterior circulations
of each side through the posterior communicating artery Venous and dural sinus anatomy
(Figure 2.24). The veins within the cranium contain approximately 70% of
The blood supply of the spinal cord will be covered in the cerebral blood volume. The cerebral blood volume, largely
Chapter 16, which deals with spinal cord strokes. sustained by the veins, plays a critical role in both arterial and
31
A-P view Figure 2.21 Large intracranial

posterior circulation arteries as they
appear on arteriograms.
Anteroposterior (A-P) view (A) and
lateral projection (B).
Superior cerebellar artery
Anterior inferior
cerebellar artery
Vertebral artery
A Basilar artery
Lateral view

Superior cerebellar
artery
Basilar artery
Anterior inferior
cerebellar artery
Posterior inferior
cerebellar artery
Vertebral artery
venous stroke syndromes. The venous blood pool is an impor- The dural venous sinuses are trabeculated, endothelial-
tant factor in the balance of intracranial pressure dynamics. lined channels whose fibrous walls are formed by the inner
The intracranial venous circulation is usually divided into the and outer layers of the dura mater. The sinuses are situated at
superficial and deep venous drainage systems.33,44,47 Most the junctions and edges of the falx cerebri and the tentorium
descriptions focus on the larger dural sinuses and veins, as cerebelli. The intracranial veins drain into the dural sinuses,
there is marked variability and redundancy in smaller venous which in turn empty into the neck veins to drain into the
channels. Although variations exist, the superficial venous superior vena cava. A system of venous lakes within the skull
drainage of the brain is typically on the right side with deep also drains into the dural sinuses. Venous blood flow distribu-
venous drainage developed from the left side. During develop- tion is often described as drainage, but pooling or retention of
ment, these lateral systems often fuse in the midline, similar to blood volume occurs due to valves and the capacitance that
the pairing of arterial structures. distinguish the veins from arteries in the brain.
32
Figure 2.22 Drawings of the

penetrating arteries to the pons
showing the pattern of arterial
Midbrain supply. A, Midline large median
arteries; B, paramedian penetra-
tors; C, penetrating arteries into the
lateral tegmentum of the pons.
Pons
C
A
Medulla
ends at the internal occipital protuberance by draining into the

confluens of the sinuses (torcular Herophili) (Figure 2.26).
The superior sagittal sinuses drain most of the blood from
the cerebral hemispheres. The posterior portion of the superior
sagittal sinus is better developed than the anterior portion. The
Right
PCA inferior sagittal sinus is smaller and shorter than the superior
Post communicating sagittal sinus and runs in the inferior margin of the falx until it
artery joins with the great cerebral vein of Galen to form the straight
BA
sinus.
PCoA
The paired transverse sinuses originate at the torcular and
Thalamogeniculate course anterolaterally along the skull between the attachments
artery
of the tentorium cerebelli. At the petrous portion of the tem-
Left
PCA poral bones, the transverse sinuses empty into the sigmoid
sinuses, which course medially and inferiorly to reach the
jugular foramina where they become the jugular veins.
Figure 2.23 Drawing showing the course and branching of the PCAs as they
Figure 2.27 is a normal MR venogram that shows the major
course around the midbrain, and branches to the temporal and parieto-occi- dural sinus structures. One of the transverse sinuses (most
pital lobes. BA, basilar artery; PCA, posterior cerebral artery; PCoA, posterior often the left) is sometimes hypoplastic or absent as it typically
communicating artery.
arises from the deep system as described above. The superior
and inferior petrosal sinuses begin at the cavernous sinuses and
The paired cavernous sinuses are located on the lateral drain into the sigmoid sinuses and the jugular veins. The
surface of the body of the sphenoid bone and are connected majority of the venous blood flow within the cranium flows
to each other by the anterior and posterior intercavernous posteriorly and drains into the sigmoid sinuses into the jugular
sinuses (Figure 2.25). The cavernous sinuses reach the superior veins and from there into the superior vena cava. These drain-
orbital fissure anteriorly and posteriorly extend to the petrous age patterns, however, are dependent on head position as the
apices. The ophthalmic and facial veins drain into the caver- jugular drainage usually collapses in the upright position.
nous sinuses. The ICAs lie within the medial walls of the The superior group of cerebral veins drains most of the
cavernous sinuses. medial surface, the superior parts of the lateral surfaces, and
The superior sagittal sinus courses in an arc from anteriorly the anterior portions of the ventral surfaces of the cerebral
to far posteriorly in the superior margin of the falx cerebri and hemispheres. The veins empty into the frontal and parietal
33
Figure 2.24 Drawing of the arterial “circle” of Willis.

Anterior communicating
artery

Posterior communicating
artery
Superior sagittal sinus

the sylvian fissure. The veins of Trolard anastamose with the
posterior ends of the middle cerebral veins and course super-
iorly to empty into the superior sagittal sinus. The veins of
Labbé anastamose with the middle cerebral veins and empty
Ophthalmic vein into the transverse sinuses. Figure 2.28 shows the major veins
Sphenoparietal sinus on the lateral surface of the cerebral hemispheres. The veins of
Trolard and Labbé are quite variable in size and location,
Intercavernous sinus
Cavernous sinus
balancing the relative sizes of the adjacent venous structures.
Figure 2.7 is a magnetic resonance imaging (MRI) scan that
Basilar plexus veins shows a hemorrhage caused by occlusion of the vein of Labbé.
Inferior petrosal sinus The deep venous system veins drain into structures at or
Superior petrosal sinus near the midsagittal plane. The paired internal cerebral veins
Sigmoid sinus originate behind the foramina of Monro and course posteriorly
Marginal sinus side by side near the midline. The thalamostriate veins course
Occipital sinus with the stria terminalis between the caudate nucleus and the
Confluence of sinuses
thalamus on each side to drain into the internal cerebral veins.
Transverse sinus
The two internal cerebral veins and the basal veins of Rosenthal
join below or behind the splenium of the corpus callosum to
Figure 2.25 Drawing of the base of the skull with the brain removed showing
the various dural sinuses. form the great cerebral vein of Galen. Figure 2.29 shows the
deep venous drainage system.
The veins that drain the brainstem and cerebellum are
regions of the superior sagittal sinus. The middle cerebral divided into three groups. The superior group drains the
veins consist of a superficial and a deep vein. The superficial superior portions of the cerebellum and the rostral and dorsal
middle cerebral veins drain the sylvian fissures and the brainstem. They empty into the vein of Galen, the basal veins of
opercula and empty into the cavernous sinuses. The deep Rosenthal, or the petrosal veins, which drain into the petrosal
middle cerebral veins form on the insular surfaces and drain sinuses. One of the superior veins, the precentral vein, is an
into the basal veins of Rosenthal. The basal veins arise on the important anatomical landmark because it separates the pons,
ventral surface of the brain lateral to the optic chiasm which lies below the vein, from the midbrain, which lies above
and course posteriorly to the cerebral peduncles where the the vein. The petrosal group of veins drains the ventral surface
interpeduncular vein connects the two basal veins. The basal of the brainstem, the superior and inferior surfaces of the
veins then course around the cerebral peduncles next to cerebellar hemispheres, and the lateral recesses of the IVth
the PCAs and empty into the great cerebral vein of Galen. ventricle. They drain into the superior petrosal sinuses or
The inferior cerebral veins drain from the inferior and lateral their tributaries. The tentorial group of veins is posteriorly
surfaces of the temporal and occipital lobes into the trans- located and drains the inferior vermis and the medial portions
verse sinuses. of the cerebellar hemispheres. They drain into the straight
Some large veins are often readily identified on cerebral sinus or lateral sinuses near the torcular.33,44 Figure 2.30
angiography. The superficial middle cerebral veins course in shows the major posterior fossa venous structures.
34
Figure 2.26 Drawing of a

midsagittal view of the skull
Superior sagittal sinus showing the major large
veins and dural sinuses.
Falx cerebri
Inferior sagittal sinus
Superior petrosal sinus

Great cerebral vein (of Galen)
Straight sinus
Transverse sinus
Inferior petrosal sinus
Confluence of sinuses
Sigmoid sinus
Occipital sinus
Jugular vein
A B Figure 2.27 (A,B) Magnetic

resonance venogram showing the
superior and inferior sagittal
sinuses, the lateral and sigmoid
sinuses, and the jugular veins.
Superior sagittal sinus Figure 2.28 Drawing of major

superficial veins seen on lateral
Rolandic vein
surface of the left cerebral
hemisphere.
Greater anastomotic vein (Trolard)
Superior cerebral veins
Middle cerebral vein (Sylvian)
Lesser anastomotic vein (Labbé)
Anterior temporal cerebral vein

Inferior cerebral veins
35
Figure 2.29 Drawing of

the deep venous drainage
system: (A) axial section
Frontal horns showing the veins and
Septal vein their relations to the lateral
of lateral ventricle
Frontal horns ventricles; (B) sagittal
of lateral ventricle section.
Thalamostriate vein
Temporal horn
Internal cerebral veins
Anterior thalamic vein
Posterior thalamic vein

Vein of Galen Atrium of
lateral ventricle
Occipital horn
Thalamostriate vein
Internal cerebral vein
Vein of Galen
Basilar vein (passing

behind midbrain)
specific carotid segments is likely determined by flow

Distribution of vascular pathology patterns, as variation in hemodynamics such as shear stress
strongly influences atherosclerosis and vascular remodeling.
Thrombosis The supraclinoid carotid arteries and the mainstem MCAs
Atherosclerotic narrowing most often occurs at the origins of and ACAs are affected less often than the ICAs in the neck
the ICAs in the neck. The remaining nuchal ICAs are seldom and the siphon in the general population,6,48,49 although in
affected, but the carotid siphon is a frequent site for ather- black and Asian patients, MCA disease is more common than
omas. This predilection for atherosclerotic narrowing of disease of the ICAs.50–54
36
Great cerebral Inferior

vein (of Galen) sagittal sinus
Internal Superior
cerebral veins sagittal sinus
Basal vein Straight sinus
(of Rosenthal) Superior
Lateral vermian vein
mesencephalic vein Confluence
Posterior of sinuses
mesencephalic vein Left transverse
sinus
Lateral brachial vein Inferior
Precentral vein vermian vein
Vein of lateral recess
of 4th ventricle
Figure 2.30 Drawing in a sagittal plane showing the brainstem and cerebellum and the major posterior fossa veins.
Anterior
communicating atherosclerosis. Atherosclerotic narrowing rarely affects the
artery ACA MCA distal superficial branches of the cerebral (ACA, MCA, PCA)
or cerebellar (PICA, AICA, SCA) arteries.
Lipohyalinosis and medial hypertrophy secondary to
Posterior
communicating hypertension affect mainly: (1) penetrating lenticulostriate
artery PCA branches of the MCAs (see Figure 2.14); (2) anterior
perforating artery branches of the ACA, often referred to
Basilar
artery
ICA as the recurrent artery of Heubner (Figure 2.32; see also
Figure 2.13); (3) penetrating arteries originating from the
AChAs (see Figures 2.15 and 2.18); (4) thalamoperforating
and thalamogeniculate penetrators from the PCAs (see
Figure 2.32); and (5) paramedian perforating vessels to
the pons, midbrain, and thalamus from the basilar artery
CCA (Figure 2.22).7,55
Vertebral
artery
At times, atheromatous plaques within parent arteries or
microatheromas within the orifices of branches cause blockage
of penetrating arteries56 (Figure 2.33). The distribution of
atheromatous branch disease is the same as that of lipohyali-
Innominate artery nosis except that atheromatous branch disease may also
Subclavian obstruct larger branches (e.g., the AChA branches of the
artery
Aortic arch ICAs and the thalamogeniculate pedicles from the PCAs).
Arterial dissection – traumatic or spontaneous tearing of a
vessel wall with intramural bleeding – usually involves the
pharyngeal portion of the carotid arteries and the VAs between
their origin and penetration into the intravertebral foramina
Figure 2.31 Drawing showing sites of predilection for atherosclerotic and in their third portion as they wind around the rostral
narrowing; black areas represent plaques. ACA, anterior cerebral artery; CCA, cervical vertebrae before penetrating the dura mater to enter
common carotid artery; ICA, internal carotid artery; MCA, middle cerebral artery;
PCA, posterior cerebral artery. the skull.12,38,57,58 In these regions, the neck arteries are mobile
and not anchored to other arteries or bony structures. Tearing
Sites of predilection for atherosclerotic narrowing in the of neck arteries is most often due to sudden stretching of the
posterior circulation include the proximal origins of the VAs arteries or direct trauma. Less common are dissections of the
and the subclavian arteries, the proximal and distal ends of the intracranial ICAs, MCAs, VAs, and basilar arteries.38,59,60
intracranial VAs, the basilar artery, and the origins of the Temporal arteritis characteristically affects the ICAs and VAs
PCAs.6,38 Figure 2.31 shows the most frequent locations of just before they pierce the dura to enter the cranial cavity, as
37
C
Figure 2.33 Drawing showing the arterial pathology in atheromatous branch
disease: (A) plaque in the parent artery obstructing a branch, (B) a junctional
plaque extending into the branch, (C) a microatheroma formed at the orifice of
Figure 2.32 Drawing showing penetrating arteries that supply the basal a branch.
ganglia and thalamus.
well as the branches of the ophthalmic arteries before they Intracerebral hemorrhage
pierce the globe.11,61 Intracerebral hemorrhage is most often caused by hyperten-
sion and has the same vascular distribution as lipohyalinosis
Embolism (Figure 2.34).28,29 In 1872, Charcot and Bouchard originally
described microaneurysms, which they believed had ruptured,
Emboli can block any artery depending on the size and
causing intracerebral hemorrhage.26,27 Sudden increases in
nature of the embolic material.62 Large emboli, often
blood pressure and blood flow can also cause these same
clots formed within the heart, can block even large
penetrating arteries to break, even in the absence of chronic
extracranial arteries, such as the innominate, subclavian,
hypertensive changes.28,29 Vascular malformations can occur
carotid, and vertebral arteries in the neck. More often,
anywhere within the brain. Cerebral amyloid angiopathy
smaller thrombi formed in the heart or the proximal
involves small arteries and arterioles within the subarachnoid
arteries embolize to block intracranial arteries, such as the
space and within the cerebral cortex.64,65 The pattern or loca-
ICAs, ACAs, VAs, basilar arteries, PCAs, and especially
tion of hemorrhage in the brain, predominantly cortical
the MCAs and their superior and inferior trunks.62 Within
or subcortical, helps distinguish amyloid angiopathy from
the anterior circulation, there is a strong predilection for
hypertensive bleeds.
emboli to go to the MCAs and their specific branches.
Small balloons released into the ICAs in experimental
animals consistently follow flow patterns to travel to Subarachnoid hemorrhage
MCA branches.63 Within the posterior circulation, emboli Aneurysms most often affect junctional regions of the larger
preferentially block the intracranial VA, the distal basilar arteries of the circle of Willis, although any branch point, such
artery, and the PCAs.38 Smaller fragments, such as tiny or as the origin of the PICAs from the VA may also be affected.
fragmented thrombi, platelet–fibrin clumps, cholesterol The ICA–posterior communicating artery junction, anterior
crystals or other fragments from atheromatous plaques, communicating artery–ACA junction, and the MCA trifurca-
and calcified fragments from heart valves and arterial tions are the most common sites. The supraclinoid ICAs,
surfaces, tend to embolize to superficial small branches of pericallosal arteries, vertebral–PICA junctions, and apex of
the cerebral and cerebellar arteries and the ophthalmic and the basilar artery are also frequent sites (Figure 2.35).23,46,66,67
retinal arteries. Arteriovenous malformations that cause the syndrome of
38
Anterior
communicating ACA
artery
f
Lobar subcortical e
hemorrhage
d MCA
Posterior
communicating c
artery b
PCA
Caudate hemorrhage
ICA
Basilar
Putaminal artery
hemorrhage a
CCA
Thalamic
hemorrhage
Vertebral
artery
Figure 2.35 Drawing that depicts the most common sites of intracranial
aneurysms; (a) posterior inferior cerebellar artery (PICA), (b) basilar artery,
(c) posterior communicating artery, (d) internal carotid artery (ICA), (e) anterior
communicating artery, and (f) bifurcation of the middle cerebral artery (MCA).
ACA, anterior cerebral artery; CCA, common carotid artery; PCA, posterior
Cerebellar
cerebral artery.
hemorrhage
ICA in the neck, Ringelstein and colleagues separated those

patients with an intra-arterial embolus to the MCA and its
branches (“occlusio supra occlusionem”) from those who had
Pontine
cortical and subcortical infarcts that were considered related to
hemorrhage diminished blood flow secondary to the ICA occlusion.68
Figure 2.36 shows common patterns of infarction in patients
with ICA occlusions. In a separate study, Ringelstein and
colleagues studied the distribution of lesions in the brain in
patients with cardiogenic cerebral embolism. Figure 2.37
illustrates various patterns of infarction associated with brain
Figure 2.34 Drawings of horizontal cerebral section and sagittal brainstem embolism based on this report.69
section, showing most common sites of intracerebral hemorrhage. In patients who have systemic hypoperfusion, in contrast,
the regions most vulnerable to ischemia are located in the
borderzones between major arterial supply zones (see
subarachnoid hemorrhage are either located in the brain,
Figure 2.6A). The situation has been likened to a watering
abutting on pial or ventricular surfaces, or situated within the
system for a field.20,70 If a hose is blocked and the pressure of
ventricular system or the subarachnoid space. Some large
water in the pump remains constant, the portion of the field
malformations are located entirely within the subarachnoid
least well supplied is at the center of the blocked hose (see
cerebrospinal fluid compartment.
Figure 2.6B). More water flows through the open or collateral
hoses to supply the edges of territory supplied by the blocked
Distribution of brain pathology hose. However, if pump pressure is reduced, water trickles
out of each hose, and only the center of supply of each hose
Ischemia receives water (see Figure 2.6C). Low pressure reduces flow
The distribution of brain lesions caused by thrombosis is not to the borderzone regions or watersheds between hoses.
easily distinguished from that owing to embolism, because in Some borderzones are cortical or cortical–subcortical while
many patients thrombosis of an artery can lead to distal artery- others are deep; the latter are usually referred to as internal
to-artery embolism. Usually, the region of ischemia tends to lie borderzones. Another way to consider the distribution of
in the center of the supply of the occluded artery. The extent damage in patients with low flow is the concept of distal
and size of the infarct depends on the location of the occlusion, fields.20 The regions that receive the least blood are those
rate of development of the occlusion, adequacy of collateral farthest from the center of the longest vessels. These distal
circulation, and resistance of brain structures to ischemia. In fields are situated at the edges of the major vessel distribu-
patients with angiographically documented occlusion of the tions and most often are located in the posterior portions of
39
A B C D
E F G
H I J
K L M
Figure 2.36 Drawings showing the most common computed tomography (CT) locations of infarcts in the anterior circulation in patients with ICA occlusions;
infarcts are shown by hatched gray: (A) wedge-shaped MCA infarct; (B) entire MCA territory; (C) superior division MCA; (D) inferior division MCA; (E) ACA; (F) ACA and
MCA; (G) striatocapsular infarct; (H) wedge-shaped, anterior watershed infarct; (I) wedge-shaped, posterior watershed infarct; (J) anterior and posterior watershed
infarcts; (K) linear internal watershed infarct; (L) oval-shaped, deep watershed infarct; (M) small white matter watershed infarct.
the cerebral hemispheres. The common borderzone infarct pressure in the vessel segments allows higher pressure
regions are shown in Figure 2.36H–M. Any vascular terri- blood flow from collaterals to fill. Such collateral flow
tory has potential collateral vessels that can provide blood patterns can actually be shown as reverse flow in the main
flow from adjacent regions. Immediately after the blockage arterial tree if the upstream artery is completely or severely
or occlusion of a vessel, the diminished downstream blocked.
40
Figure 2.37 Drawings of computed tomography (CT) scans that

show the most common infarct patterns in patients with embolic
strokes. Adapted from Ringelstein EB, Koschorke S, Holling A, et al.
Computed tomographic pattern of proven embolic brain infarctions.
Ann Neurol 1989;26:759–765.
Intracerebral hemorrhage Physiology and pathophysiology of brain

The most common brain locations for hypertensive intracer- ischemia and hemorrhage
ebral hemorrhages are as follows: lateral ganglionic (putaminal
or pallidal) and capsular (40%), thalamus (12%), lobar white Ischemia
matter (15–20%), caudate nucleus (8%), pons (8%), and cere-
bellum (8%)29,71 (see Figure 2.34). Such bleeding sites are often Normal metabolism and blood flow
supplied by perforatoring arteries that have become frail due to The brain is a metabolically very active organ. Despite its
chronic hypertension. Bleeding does not usually conform to relatively small size, the brain uses about one-quarter of the
territories supplied by larger arteries since hemorrhages often body’s energy supply. Brain cells depend mainly on oxygen and
dissect across arterial boundary territories. Hemorrhages sugar to survive. Unlike other body organs, the brain uses
owing to vascular malformations have no special predilection glucose as its sole substrate for energy metabolism. Glucose is
sites but are most often either subcortical or near the brain oxidized to carbon dioxide (CO2) and water (H2O). Glucose
surface. Hemorrhages caused by amyloid angiopathy are metabolism leads to conversion of adenosine diphosphate
usually lobar, often occipital, and seldom affect the basal (ADP) into adenosine triphosphate (ATP). A constant supply
ganglia or posterior fossa structures.65,72 of ATP is needed to maintain neuronal integrity and to keep
Hemorrhages related to illicit drug use, especially cocaine the major extracellular cations Ca2+ (calcium ions) and Na+
and amphetamines, have the same general distribution as (sodium ions) outside the cells and the intracellular cation K+
hypertensive hemorrhages, probably because the mechanism (potassium ions) within the cells. Production of ATP is much
of bleeding is an acute increase in blood pressure. Patients who more efficient in the presence of oxygen. Although in the
develop intracranial hemorrhages after using cocaine have a absence of oxygen anaerobic glycolysis leads to formation of
much higher frequency of aneurysms and vascular malforma- ATP and lactate, the energy yield is relatively small, and lactic
tions than hemorrhages that develop after amphetamine use.73 acid accumulates within and outside of cells.76 The brain
Hemorrhages in patients who are being treated with anti- requires and uses approximately 500 ml of oxygen and
coagulants preferentially involve the cerebral white matter 75–100 mg of glucose each minute, a total of 125 g of glucose
and the cerebellum.74,75 each day.77
41
These requirements for oxygen and glucose translate into a CBF

need for lots of oxygenated blood containing adequate sugar.
Even though the brain is a relatively small organ, accounting 100 g per
for only 2% of adult body weight, the brain uses approximately % min %
20% of the cardiac output when the body is resting.76 Cerebral
100 50
blood flow (CBF) is normally approximately 50 ml for each
100 g of brain tissue per minute, and cerebral oxygen con-
80 40
sumption, usually measured as the cerebral metabolic rate for
oxygen (CMRO2), is normally approximately 3.5 ml/100 g per
minute.78 By increasing oxygen extraction from the blood- 60 30
stream, compensation can be made to maintain CMRO2 until
CBF is reduced to a level of 20–25 ml/100 g per minute.76 40 20
Electrical function affected
Positron emission tomography (PET) can measure CBF,
CMRO2, and oxygen extraction fraction (OEF) and the cere- 20 10 Electrical failure complete
bral metabolic rate for glucose (CMRg1) in various brain Release of potassium
regions of interest.78,79 PET scanning is discussed in more 0 0 (and cell death)
detail in Chapter 4. Figure 2.38 Thresholds of brain ischemia. CBF, cerebral blood flow.
Brain energy use and blood flow depend on the degree of
neuronal activity. In 1890, Roy and Sherrington first demon-
strated the ability of the brain to increase local blood flow in 20 ml/100 g per minute, electroencephalographic (EEG) activ-
response to regional changes in neuronal activity.80,81 PET and ity is affected. The cerebral metabolic rate of oxygen (CMRO2)
functional MRI show that using the right hand increases metab- also begins to fall when CBF is diminished below 20 ml/100 g
olism and CBF in the left motor cortex. Clearly, it is critical per minute. At levels below 10 ml/100 g per minute, cell
for survival of brain tissue that there are systems to maintain membranes and functions are severely affected. Neurons
CBF despite changes in systemic blood pressure. The capacity cannot survive for long at blood flows below 5 ml/100 g per
of the cerebral circulation to maintain relatively constant levels minute. Ischemic injury is the product of the severity and
of CBF despite changing blood pressure has traditionally been duration of decreased blood flow, offset by collateral circula-
termed autoregulation. CBF remains relatively constant when tion and also modified by the ischemic tolerance or capacity of
mean arterial blood pressures are between 50 and specific brain tissue to sustain injury.
150 mmHg.76 When blood pressure is chronically raised, When neurons become ischemic, a number of biochemical
both the upper and lower levels of autoregulation are raised, changes potentiate and enhance cell death: K+ moves across the
indicating a higher tolerance to hypertension but also cell membrane into the extracellular space, and Ca2+ moves
increased sensitivity to hypotension.82 into the cell, where it greatly compromises the ability of
Mean blood flow velocities as measured by transcranial intracellular membranes to control subsequent ion fluxes and
Doppler (TCD) within the intracranial arteries range from 35 causes mitochondrial failure;78 normally, there is a 10-fold
to 75 cm per second but vary considerably with age, sex, blood gradient difference between extracellular and intracellular
pressure, hematocrit, and blood vessel location.83 When CBF (cytosolic) Ca2+. Decreased oxygen availability leads to pro-
increases or an artery narrows, the velocity in that segment of duction of oxygen molecules with unpaired electrons, termed
artery increases. At first glance, increased velocity in response oxygen-free radicals. These free radicals cause peroxidation of
to a reduction in luminal diameter seems paradoxical. One fatty acids in cell organelles and plasma membranes, causing
must try, however, to visualize a simple everyday example of severe cell dysfunction.84,85 With decreased oxygen availabil-
velocity of liquid flow – an ordinary garden hose. When using a ity, anaerobic glycolysis leads to an accumulation of lactic acid
hose to wash off a pavement or a patio, to generate a high and a decrease in pH. The resulting acidosis also greatly
pressure jet of water, the nozzle is turned to reduce the luminal impairs cell metabolic functions.
diameter. The narrower the nozzle lumen, the more pressure in The activity of neurotransmitters, often referred to as
the stream until the lumen is nearly effaced, at which time excitatory neurotransmitters (glutamate, aspartate, and
water dribbles out, and velocity becomes greatly reduced. This kainic acid), is significantly increased in regions of brain
analogy will be useful to recall in Chapter 4, when we discuss ischemia.85–88 Hypoxia, hypoglycemia, and ischemia all
transcranial Doppler measurements of blood flow velocities in contribute to cause energy depletion and an increase in
proximal segments of the intracranial arteries. glutamate release but a decrease in glutamate uptake. This
increased availability of glutamate causes vulnerable
Local brain effects of ischemia neurons to receive toxic exposure to glutamate, thereby
When blood flow to a brain region is reduced, survival of the increasing the likelihood of cell death. Glutamate entry
at-risk tissue depends on the intensity and duration of the opens membranes and increases Na+ and Ca2+ influx into
ischemia and the availability of collateral blood flow. Animal cells. Large influxes of Na+ are followed by entry of chloride
experiments provide estimates of thresholds of brain ions and water, causing cell swelling and edema. Glutamate
ischemia (Figure 2.38).76 At blood flow levels of approximately is an agonist at both N-methyl-D-aspartate (NMDA) and
42
non-NMDA (kainate and quisqualate) receptor types, but restoration of either adequate blood flow or other as yet
only NMDA receptors are linked to membrane channels unknown conditions before resuming full life.”85 Some
with high calcium permeability.87 Knowledge of these neurons are thought to be more vulnerable to hypoxia and
changes in the neuronal and extracellular spaces is impor- decreased fuel supply than other neurons, termed selective
tant to recall when treatment of acute stroke patients is vulnerability.86 Recent advanced imaging approaches to
discussed in Chapter 6. stroke with multimodal computed tomography (CT) and
These aforementioned local metabolic changes cause a MRI often refer to these penumbral zones as regions at-risk
self-perpetuating cycle of changes that lead to increasing of ischemic infarction as it remains difficult to standardize
neuronal damage and cell death. Changes in ionic concentra- penumbral definitions across various imaging modalities
tions of Na+, K+, and Ca2+; release of oxygen-free radicals; and measures.
acidosis; and release of excitatory neurotransmitters further
damage cells, leading to more local biochemical changes,
which in turn cause more neuronal damage.87,88 At some Arterial occlusion and reaction to the occlusive
point, the process of ischemia becomes irreversible, despite process
reperfusion of tissues with adequate oxygen and glucose-rich Brain ischemia should not be viewed as a static anatomic–
blood. At times, although the severity of ischemia is insuffi- pathological process. It is usually an incredibly dynamic,
cient to cause neuronal necrosis, ischemia may nevertheless set often unstable, condition. Brain tissue, in imminent danger
in motion a process of programmed cell death referred to as of irreversible death, nevertheless often recovers remarkably
apoptosis.89 well, leaving no trace of its previous precarious situation.
The degree of ischemia caused by blockage of an artery To treat patients optimally, physicians must understand
varies in different zones supplied by that artery. In the center of the various factors that affect outcome. The discussion of
the zone, blood flow is lowest and ischemic damage is most pathophysiology has so far centered on the function and
severe. This region of the most severe damage is often referred metabolism of local regions of brain tissue. To understand
to as the core of the infarct. On the periphery of the affected the variety of factors affecting outcome, we now turn to
vascular territory, collateral blood flow allows continued a more macroscopic view of both the process of arterial
delivery of blood. The capacity of collateral circulation also occlusion and the way in which occlusive changes are
markedly varies across individuals. Referring to Figure 2.38, handled by the body.
metabolism at the center of blood supply may be reduced Vascular occlusion most often begins with formation of
sufficiently to cause cell necrosis (0–10 ml/100 g/minute), atherosclerotic plaques within extracranial and large intra-
whereas at the periphery, supplies of 10–20 ml/100 g per cranial arteries. These plaques contain a mixture of lipid,
minute might stun the brain, causing electrical failure but not smooth muscle, fibrous and collagen tissues, macrophages,
permanent cell damage. The zone of dysfunctional, but not and inflammatory cells. Plaques may enlarge quickly when
dead, brain surrounding the center of infarction has tradition- hemorrhages occur within the plaques. When a critical
ally been referred to as the ischemic penumbra (Figure 2.39). plaque size and significant encroachment on the lumen
Garcia and Anderson eloquently describe this region as develop, the atherosclerotic process often accelerates.
follows: “Penumbral neurons are thought to be paralyzed in a Reduced luminal area and the bulk of the protruding plaque
shadowy state between life and death, merely awaiting the alter the physical and mechanical properties of blood flow
and create regions of local turbulence and stasis. Platelets
often adhere to irregular plaque surfaces. Secretion of
Penumbra
chemical mediators within platelets and within the under-
lying vascular endothelium causes aggregation and further
adherence of platelets to the endothelium. ADP, epinephr-
ine, and collagen can all increase platelet aggregation.90
Activated platelets release ADP and arachidonic acid. In
the presence of the enzyme cyclooxygenase, arachidonic
acid is metabolized to prostaglandin endoperoxides, which
can be converted by thromboxane synthetase to thrombox-
ane A2, a potent vasoconstrictor and inducer of further
platelet aggregation and secretion.3 At the same time, the
vascular endothelium may secrete prostacyclin, a potent
vasodilator and inhibitor of platelet aggregation.91 Both vas-
cular patency and the formation of platelet–fibrin clots are
Infarct core influenced by the balance between thromboxane A2, prosta-
Figure 2.39 Cartoon showing the core and penumbra of a brain infarct. cyclin, and other factors. Platelets begin to stick together and
The darkest region represents the core – tissue already infarcted. The adhere to the endothelial lining of the plaque. A “white clot”
surrounding gray zones represent areas with decreased blood flow but capable
of recovery if the blood supply improves. In the most peripheral gray zone, composed of platelets and fibrin develops (Figure 2.40; see
the blood supply decrement is least severe. also Figure 2.2C).
43
Figure 2.40 Phase microscope image of a white fibrin–platelet thrombus

Figure 2.41 Ulcerated internal carotid artery (ICA) plaques in specimens of
(black arrow) formed in a high flow system. Courtesy of S H Hanson and C H
arteries removed at surgery. A black and white version of this figure will appear
Kessler, Emory University, Division of Hematology.
in some formats. For the color version, please refer to the plate section.
necropsy. The specimen contains a large mobile red thrombus,

a part of which had embolized to the brain. Within a period of
1–2 weeks, thrombi organize and become more adherent and
fragments are less likely to break off and embolize. A variety of
different materials – cholesterol crystals, calcified plaque frag-
ments, white clots, and red thrombi – can form the substance
of intra-arterial emboli. Recent analyses of retrieved thrombi
have shown mixtures of red and white thrombi, likely due to
associated conditions and the hemodynamic milieu as well as
sampling variation in such specimens.
Atherosclerotic plaques and vascular stenosis cause brain
ischemia in a variety of ways. Progressive intimal thickening
leads to stenosis or occlusion of the artery, resulting in reduced
distal blood flow. Stasis of blood flow enhances the formation
of thrombi that often embolize. Physical factors are clearly
important in the formation, lysis, clearance, and washout of
Figure 2.42 Phase microscope image of a red thrombus, composed of fibrin thromboemboli. Blood flow at arterial bifurcations is complex
and erythrocytes, formed in a thrombogenic system, in a vessel with a low flow even in normal non-stenotic arteries. Eddies, turbulence, flow
rate. Courtesy of S H Hanson and C H Kessler, Emory University, Division of separation, and vortices are common and vary with location
Hematology.
along the arteries.92 As an artery narrows, blood flow velocity
increases within the center of the artery and flow separation
Plaques often interrupt the endothelial lining of arteries becomes more prominent.92 Flow is reduced in some parts of
and ulcerate. Figure 2.41 shows ulcerated irregular plaques the artery, especially on the outer perimeter of the residual
within specimens of carotid arteries removed at surgery. lumen. When subtotal or complete occlusion of an artery
Breaches in the endothelium allow cracks and fissures to develops, the blood-stream flow diminishes because of reduced
form, allowing contact of the constituents of the plaque with volume of flow, and blood flow velocity also is decreased.92–94
the blood within the lumen. Tissue factor, an important sti- Antegrade perfusion becomes less effective. This reduced per-
mulator of the body’s coagulation system, is released. The fusion and pressure decreases washout and throughput of
coagulation cascade is activated by this contact and a “red emboli, especially in remote borderzone portions of the brain
thrombus” composed of erythrocytes and fibrin forms within circulation.95–97 Hypoperfusion and embolism interact and
the lumen (Figure 2.42; see also Figure 2.2C). Platelet secretion complement each other to promote and enhance brain
can also activate the serine proteases that form the body’s infarction.93,94
coagulation system and also promotes the formation of red
clots. When white or red thrombi first form, they are poorly Thrombus formation
organized and only loosely adherent. They often propagate and Thrombi form in situ when the body’s coagulation system has
embolize. Figure 2.4 shows an occluded carotid artery found at been activated and the blood is hypercoagulable. In some
44
patients with hypercoagulability, red thrombi form simultan- Intrinsic

eously or sequentially in multiple, systemic extracranial and
intracranial arteries and veins. In other patients with arterial XIIa
lesions (e.g., arterial atherosclerotic plaques or dissections), the XIa
process of occlusive thrombosis is accelerated at sites of vas- Extrinsic
cular disease. Hypercoagulability can be a lifelong hereditary IXa tissue factor
problem. Systemic diseases, such as cancer, regional enteritis,
VIIIa VIIa
and thrombocytosis, can cause increased clotting. The process
of atherothrombosis (e.g., in the coronary or cerebrovascular X
systems) can also activate serological coagulation factors that
promote further thrombosis.98–102
Much of the treatment of patients with thromboembolic Xa
stroke concerns attempts to affect or reverse the coagulation
process or to facilitate clot lysis or removal. Clinicians treating
patients with ischemia should be familiar with the general Factor Va, Ca2+ Prothrombinase
Phospholipid complex
features of blood coagulation to effectively choose and monitor
antithrombotic and thrombolytic therapies.
The final step in the coagulation cascade is the conversion Prothrombin Thrombin
of the soluble protein fibrinogen into insoluble polymers
termed fibrin. These strands of fibrin form a network of fibers Fibrinogen Fibrin
that entangle formed blood elements (i.e., platelets and ery- Figure 2.43 Diagrammatic scheme of extrinsic and intrinsic coagulation
throcytes) into a clot. Fibrin is quite adhesive and has the systems.
capability of contracting. The fibrinogen-to-fibrin reaction
occurs when factor II, prothrombin, is converted to thrombin.
The amounts of circulating fibrinogen and prothrombin are Genetically transmitted disorders can also lead to hypercoa-
important in these reactions. gulability. One common inherited disorder leads to functional
Prothrombin can be activated in two different ways: In the resistance to the anticoagulant effects of activated protein C.103
so-called extrinsic system of coagulation, a tissue or endothe- This genetic defect is termed the factor V Leiden mutation and is
lial injury releases thromboplastic substances, known as tissue caused by a point mutation in factor V.104 Another genetic
factors, which in turn cause both platelet activation and activa- disorder that predisposes to thrombosis is caused by a mutation
tion of some of the blood serine protease coagulation factors, in the prothrombin gene.105 These mutations in the prothrom-
especially factors V and VII. Tissue factor forms a complex bin and factor V genes are common in patients who develop
with factor VIIa; the tissue factor-VIIa complex converts factor cerebral venous thrombosis and phlebothromboses, especially if
X to Xa. Factor Xa activates a prothrombinase complex com- they also take oral contraceptives.106
posed of activated factor V, Ca2+, and phospholipids, which in Key components in the coagulation system are factor Xa,
turn with factor Xa catalyzes the reaction of prothrombin to prothrombin, and thrombin. Factor Xa is especially important
thrombin. Activation of platelets causes them to agglutinate, to since it is the focal point at the intersection of both the intrinsic
adhere to the injured vessel wall, and to release various intra- and extrinsic portions of the coagulation cascade. Heparins
cellular substances, which in turn activate the coagulation cause a conformational change in antithrombin III, which
system.98–100 increases its ability to inactivate factor Xa. Warfarins inhibit
The complementary intrinsic coagulation system refers the action of vitamin K necessary for the biosynthesis of pro-
to blood-coagulation factors that circulate in inactive forms thrombin and factor X. Researchers and clinicians are now
(factors V, VIII [antihemophilic globulin], IX, X, XI, XII) and exploring the potential for using agents that inactivate factor
are intrinsic to the blood. Activation of factor XII from an inert Xa or directly inhibit thrombin generation and function.
precursor form to an activated form triggers a series of reac- Naturally occurring factors also exist that act to lyse clots
tions, described as the coagulation cascade in which the various once they are formed. Tissue plasminogen activator and other
blood-clotting factors are sequentially converted to their active substances activate plasminogen to form plasmin, a potent
enzymatic forms. Ultimately, these reactions lead to activation fibrinolytic enzyme. Plasminogen is also activated by various
of factor X, which catalyzes the prothrombin → thrombin coagulation factors, such as factor XII, so that the process of
reaction.100–102 Figure 2.43 is a simplified diagram of the coagulation itself activates the thrombolytic system. Various
coagulation reactions. Thrombin, in turn, in addition to plasmin inhibitors (“antiplasmins”) are also present.102,107
converting fibrinogen to fibrin, has an important influence Pathologists and hematologists recognize and describe
on blood platelets, causing them to swell, aggregate, and release three types of thrombi101:
substances that affect vascular tone and blood coagulability. 1. Red thrombi are composed mostly of red blood cells and
Also important are various natural inhibitors of coagula- fibrin; they form in areas of slowed blood flow. Their
tion: antithrombin III, protein C, and protein S. Deficiencies in formation does not require an abnormal vessel wall or
any of these serum proteins can cause increased coagulability. tissue thromboplastin (see Figure 2.42).
45
2. White thrombi, in contrast, are composed of platelets and determinants of blood viscosity are the hematocrit and the
fibrin and do not contain red blood cells (see Figure 2.40). fibrinogen levels.110–112 In patients with hematocrits in the
White clots form almost exclusively in areas in which the range of 47–53%, lowering of the hematocrit by phlebotomy
arterial wall or endothelial surface is abnormal, to below 40% can increase CBF by as much as 50%.112 Blood
characteristically in fast-moving bloodstreams. pressure is also very important. Elevation of blood pressure
3. Disseminated fibrin deposition in small vessels. except at malignant ranges increases CBF. Surgeons take
advantage of this fact by injecting catecholamines to raise
These types of thrombi are distinct and are affected by blood pressure and flow during the clamping phase of carotid
different therapeutic agents. In many cases, the thrombus endarterectomy. Low blood pressure significantly reduces
begins as a white platelet–fibrin clot and then a red thrombus cerebral blood flow. In some patients, the balance is so tenuous
is laid down as a cap over the initial platelet mass.101 that simply sitting in bed or standing lowers collateral pressure
When a major artery occludes, a crisis ensues. Pressure enough to induce symptoms.113,114 Low blood and fluid
drops distal to the occlusion, and the brain region supplied by volume also limit available blood flow in collateral channels.
that vessel is acutely deprived of blood. Diminished blood Many older individuals limit their fluid intake, especially in the
flow in turn activates protective mechanisms that help restore evening, to avoid getting up at night to urinate. After the
needed blood flow to the ischemic region. Low pressure helps stroke, there may not have been any fluid intake because of
to draw blood from higher pressure regions. Collateral swallowing difficulty or lack of feeding during the trip to the
circulation is allowed to enter the downstream territory hospital and the initial hospital encounters.
from adjacent vascular territories. Ischemic cell damage
causes release of lactic acid and other metabolites. The result- Serological factors
ing local tissue acidosis leads to vasodilation, augmenting
The blood functions as a carrier of needed oxygen and other
regional CBF.108 If brain tissue is deprived of blood and
nutrients. Hypoxia is clearly detrimental because each milliliter
needed nourishment for too long, it dies. At times, there are
of blood delivers a less-than-normal oxygen supply.115 Low
varying grades of ischemia, ranging from irreversible cell
blood sugar similarly increases the risk of cell death. Higher-
death in the most deprived zone to a reversible situation of
than-normal blood sugar also can be detrimental to the
diminished electrical activity but normal or only slightly
ischemic brain.116,117 Elevated serum calcium levels118,119 and
elevated extracellular potassium concentration in the threat-
high blood-alcohol content120 are also potential important
ened ischemic penumbral zone.71,85,86,108,109 The severity of
detrimental variables. These factors are also discussed in
the ischemic crisis depends on the rate of vascular occlusion.
Chapter 6 on treatment.
A vessel that gradually occludes may already have stimulated
abundant collateral circulation so that final occlusion pro-
Changes within the obstructing vascular lesion
duces less stress on the system.
Embolic occlusive thrombi do not adhere to the vessel wall of
Factors that affect tissue survival the recipient artery and frequently move on. The moving
The survival of the brain regions at risk depends on a number embolus can block a more distal intracranial artery, causing
of factors: (1) the adequacy of collateral circulation; (2) the added or new ischemia, or it may fragment and pass through
state of the systemic circulation; (3) serological factors; the vascular bed. Clot formation activates an endogenous
(4) changes within the obstructing vascular lesion; and thrombolytic system that includes tissue plasminogen activator
(5) resistance within the microcirculatory bed; (6) brain (tPA).102,107 Inhibitors of tPA are also present. Sudden obstruc-
edema and increased intracranial pressure. tion of a vascular lumen can cause reactive vasoconstriction
(spasm), which in turn causes further luminal compromise.
Adequacy of the collateral circulation Thrombolysis, passage of clots, and reversal of vasoconstriction
Variation in collateral circulation due to vascular capacity or all promote reperfusion of the ischemic zone. If reperfusion
patterns at the circle of Willis and in leptomeningeal or pial occurs quickly enough, the stunned, reversibly ischemic brain
vessels can radically alter the outcome of ischemic stroke. may recover quickly. The occlusive clot may propagate further
Although persistent fetal patterns are often described at the proximally or distally along the vessel, blocking potential collat-
circle of Willis, serial imaging studies show dynamic changes eral channels. The distal end of the thrombus can also break loose
in vascular segments of this structure during adult life due to and embolize to an intracranial receptive site. Hypercoagulable
changes in blood flow. The specific determinants of collateral states promote such extension of thrombi.
grade or capacity remain an area of focused research due to
their importance in stroke outcomes. Hypertension or diabetes Resistance within the microcirculatory bed
diminishes blood flow in smaller arteries and arterioles and so The vast majority of CBF does not occur in the large macro-
reduces the potential of the vascular system to supply blood scopic arteries at the base of the brain or along the surface.
flow to the needy region. Most flow occurs through microscopic-sized vessels: the arter-
ioles, capillaries, and venules.102 Resistance to flow in these
State of the systemic circulation small vessels is affected by prior diseases, such as hypertension
Cardiac pump failure, hypovolemia, and increased blood and diabetes, which often cause thickening of arterial and
viscosity all reduce CBF. The two most important arteriolar walls. Experimental animals and patients that have
46
been hypertensive before a vascular occlusion fare worse than Brain edema and increased intracranial pressure also cause
individuals previously normotensive, presumably because headache, decreased consciousness, and vomiting.123 Pressure
of these microcirculatory changes. Both hyperviscosity and shifts and herniation cause pressure-related damage to adja-
diffuse thromboses within the capillaries and microvessel bed cent tissues and signs of dysfunction of the compressed
greatly reduce flow through the microcirculation. Ischemic structures.32,123,124 Because pressure shifts and herniations
insults may produce biochemical changes that lead to platelet are more common after intracerebral hemorrhage, due to the
activation, clumping of erythrocytes, and plugging of the additional presence in the brain of an extra mass of tissue
microcirculation. Ames referred to these changes as causing (hematoma), we discuss herniations further in the discussion
a “no reflow” state in the microvascular bed, even when of intracerebral hemorrhage.
large arteries are reperfused.121 In general, studies of CBF
are sensitive to changes in resistance in the microcirculatory Events during the first three weeks after
bed. Remember that flow is inversely proportional to
resistance in the vascular bed, the majority of which is vascular occlusion
microcirculatory. Experience shows that the tenuous balance created by occlu-
sion of a major artery is temporary and usually resolves in 2–3
Brain edema and increased intracranial pressure weeks at most. During this period, any systemic changes, such
as decrease in fluid volume or positional or pharmacologically
Edema and pressure changes within the brain and cranial cavity
mediated drops in blood pressure, can cause worsening of
also influence survival of brain tissue and patient recovery after
symptoms. By 3 weeks, either the brain tissue has died, causing
vascular occlusions. There are two types of brain edema: (1)
a brain infarct, or collateral sources of blood flow develop that
water accumulation inside cells, termed cytotoxic edema; and
adequately supply the region at risk. By 2–3 weeks, collateral
(2) fluid within the extracellular space, often termed vasogenic
circulation stabilizes, and the patient is less vulnerable to posi-
edema.122 Extracellular edema is also often referred to as wet
tional or circulatory changes. In addition to causing ischemia
edema because in such cases, the cut surface of the brain oozes
through low perfusion, the occlusive thrombus, which at first
edema fluid, whereas intracellular (cytotoxic) edema is termed
loosely adheres to the vessel wall, can propagate distally or can
dry edema.122 Cytotoxic edema is caused by energy failure, with
fragment and embolize to a distal artery. By 2–3 weeks, the clot
movement of ions and water across the cell membranes into cells.
has become more adherent and has much less tendency to
Extracellular edema is influenced by hydrostatic pressure factors,
embolize. Most studies of patients with anterior125,126 and
especially increased blood pressure and blood flow, and by
posterior circulation ischemia38,127–131 show a low frequency
osmotic factors. When proteins and other macromolecules
of progression of acute ischemic deficits after 2 weeks.
enter the brain extracellular space because of breakdown of the
During the hours, days, and early weeks after a vascular
blood–brain barrier, they exert an osmotic gradient pulling water
occlusion, the question of death or survival of at-risk brain
into the extracellular space. This vasogenic edema accumulates
tissue can be viewed as a clash between factors acting to worsen
more in the cerebral and cerebellar white matter because of the
ischemia and natural body responses that prevent or limit
difference in compliance between gray and white matter.
ischemia. Table 2.1 summarizes these “good guys” versus
Brain swelling caused by cytotoxic edema means a large
“bad guys” responses, which are useful to keep in mind when
volume of dead or dying brain cells, which implies a bad out-
treatment is discussed. Clinicians hope to build on the body’s
come. On the other hand, edema within the extracellular space
natural defenses and counteract the factors that promote
does not necessarily imply neuronal injury, and fluid in the
ischemia.
extracellular compartment can potentially be mobilized and
removed. Severe edema may cause gross swelling of the brain;
shifts in position of brain tissue, with potential pressure Table 2.1 Balancing of factors after vascular occlusion
damage; and herniation of brain contents from one compart-
ment to another. Factors promoting ischemia Responses limiting ischemia
Intracranial pressure may also be increased, leading to Decreased blood flow due to Opening of collateral vascular
increased morbidity and decreased CBF. When intracranial occlusion channels
pressure is increased, the pressure in the venous sinuses and
draining veins must also increase if blood is to be drained Embolization of clot Passing and fragmentation of
normally from the cranium. There must be a gradient between emboli
venous pressure and intracranial pressure for drainage to Activation of coagulation Activation of thrombolytic
occur. Also, for tissue perfusion to occur, arterial pressure factors and inhibitors of factors
must exceed venous pressure. Blood flow is compromised in thrombolysis
the presence of arterial and venous occlusions. When the Propagation of clot Lysis of clot
intracranial venous system contains occlusions, venous pres-
sure is increased. The limited drainage often causes fluid to Decreased blood flow due to Improvement in general
back up into the brain, causing vasogenic edema. Increased hypotension, hypovolemia, medical condition, especially
low cardiac output after correction of
intracranial pressure places an additional stress on the system,
abnormalities
forcing even higher the flow values required for tissue survival.
47
This process of shifting vulnerability translates clinically

into fluctuating variable symptoms and signs during the early
period after a vascular occlusion. Acute blockage of an artery
often translates into the sudden onset of symptoms. After
vascular occlusion, a weighing of the balance of positive and
adverse factors toward the adverse side causes transient deficits
or causes fluctuating, stepwise, or gradual worsening of
neurological symptoms and signs. Sudden worsening is often
related to distal embolization.
Hemorrhage into the brain parenchyma is often preceded by
hypertensive damage to small cerebral penetrating arteries and
arterioles. Small aneurysmal dilatations, first hypothesized by
Charcot and Bouchard in the 1870s, pepper the penetrating
vascular territories of hypertensive patients26,27 and in some
patients represent weak points that rupture under increased
arterial tension. In most patients, abrupt elevation in blood
pressure causes rupture of small penetrating arteries that had
no prior vascular damage.28,29 Leakage from these small vessels
produces a sudden but local pressure effect on surrounding
capillaries and arterioles, causing them in turn to break.132 An
avalanche-type effect ensues, in which vessels at the circum-
ference break, adding volume to the gradually enlarging
hemorrhage (Figure 2.44). The accumulation of blood along
the circumference of the hematoma is like a snowball rolling
downhill, gathering volume along its outer surfaces as it des-
cends. High blood pressure and this avalanche effect enlarge
the hemorrhage, while mounting local tissue pressure acts as a
tamponade to the bleeding.
Trauma, bleeding disorders, and degenerative changes in
congenitally abnormal blood vessels within vascular malfor-
mations also may initiate intracerebral bleeding, which then
progresses in a manner similar to hypertensive intracerebral
hemorrhage. The gradual increase in size of the hematoma
translates clinically into gradual worsening of symptoms and
signs until the hematoma attains its final size. Hematomas can
stop enlarging and may drain themselves by emptying into the Basilar
ventricular system or the cerebrospinal fluid (CSF) at the pial artery
surface. Figure 2.44 Drawing illustrating avalanche-type effect in pontine hemor-
If the hemorrhage becomes sizable, the increase in intra- rhage, showing gradual development of hemorrhage due to rupture of small
vessels on the periphery of the hemorrhage.
cranial volume must increase intracranial pressure. When
intracranial pressure rises, the venous pressure in the draining
dural sinuses increases pari passu. To perfuse the brain, the
arterial pressure must rise to produce an effective arteriove- lesion,132,133 to the effects of the lesion on blood flow and
nous difference. The patient with intracerebral hemorrhage metabolism, and, in large hemorrhages, to shifts in brain
may have a markedly elevated blood pressure because of the contents and herniations. Effects caused by masses in patients
hemorrhage, not necessarily reflecting the true level of pre- with hematomas are more common than in patients with
morbid blood pressure. Although lowering this pressure does ischemia because an extra volume of substance has been
help to stop bleeding, caution must be exercised because the added (blood in the hematoma) in addition to the surrounding
elevated pressure also serves to perfuse the areas of the brain edema. Most often, pressure effects in hemispheral hematomas
not damaged by the hemorrhage. result in a shift of the midline without herniation of brain
Patients with intracerebral hemorrhage often worsen contents. The brain is compartmentalized by bony fortresses
during the first 24–48 hours after their initial symptoms. This (anterior, middle, and posterior fossas) and by dural structures
worsening can be explained by continued bleeding but most (falx cerebri and tentorium cerebelli), which, under normal
often is related to the development of edema around the circumstances, contain their usual contents. When mass
48
Posterior
cerebral
artery
A B
A B
Anterior
cerebral
artery
C D
C D
Figure 2.46 Drawing illustrating infarcts due to compression of arteries: (A)
Normal anatomy showing posterior carotid artery (PCA) crossing up and over
the edge of the tentorium; (B) infarction of medial temporal lobe due to
compression of PCA between herniated uncus and tentorium; (C) anatomy
showing anterior carotid artery (ACA) in relation to falx; (D) infarction of medial
frontal lobe, due to compression of ACA against the falx cerebri.
compress the brainstem (see Figure 2.45D); and (5) downward

A
herniation of the cerebellar tonsils through the foramen
B magnum, compressing the medulla and upper cervical spinal
cord (see D in Figure 2.45E).
Shifts in brain contents can also lead to compression or
stretch of arteries and infarction in areas of supply and sec-
ondary hemorrhages. The most common loci of secondary
D
vascular changes leading to infarction involve the PCAs
where they pass between the tentorium and the medial tem-
E
poral lobe and the ACAs adjacent to the falx (Figure 2.46).
Distortion of the upper brainstem at the tentorial opening
Figure 2.45 Drawings illustrating shifts and herniations. Displacement of
brain tissues due to mass-producing strokes is illustrated by patients with
often leads to secondary hemorrhages in the brainstem.
hematomas. (A) Basal ganglionic hematoma causes compression of the These usually involve the midline and paramedian vessels
ipsilateral ventricle and shift of the midline to the opposite side. (B) Deep and are called Düret hemorrhages, after the French clinician
hematoma causes uncal herniation. The medial temporal lobe exerts pressure
on the upper brainstem. (C) Frontal hematoma causes herniations of the
and researcher who first described them.134 A necropsy
cingulum under the falx cerebri. (D) Cerebellum hematoma causes increased specimen of a Düret hemorrhage is shown in Figure 2.47 and
posterior fossa pressure with herniation of the cerebellum (E) through the a drawing of another Düret hemmorhage is shown in
foramen magnum. These patterns are also illustrated in E.
Figure 2.48B.
The ventricular system may also be compressed at vari-
effects are severe, brain tissue bulges or spills out of its usual able sites. Hematomas in the putamen or cerebral lobes
abode into a different compartment – a process called may distort the foramen of Monro, causing dilatation of
herniation.30–32,124 the contralateral lateral ventricle. Thalamic hematomas
Brain shifts and herniations and their effects are shown in often obstruct and compress the IIIrd ventricle, leading
Figure 2.45. The most common are: (1) herniation of the to hydrocephalus of both lateral ventricles. Cerebellar
temporal lobe through the tentorial notch, to compress the hemorrhages can compress the IVth ventricle or cerebral
midbrain (see Figure 2.45A); (2) symmetric, downward aqueduct, leading to obstructive hydrocephalus of the
pressure by the swollen cerebral hemispheres on the rostral third and lateral ventricles. Shifts in brain contents,
brainstem, causing elongation (see Figure 2.45B); (3) hernia- herniations, and secondary infarctions, as well as Düret
tion of the anterior medial frontal lobe, usually of the cingulate hemorrhages and hydrocephalus, all cause clinical worsen-
gyrus, under the falx cerebri (see Figure 2.45C); (4) herniation ing of signs and symptoms. Intracerebral hemorrhages are
of the cerebellum upward through the tentorial notch, to discussed in detail in Chapter 14.
49
Figure 2.47 A necropsy specimen of a Düret midbrain hemorrhage. A left

subdural hematoma was present on the lateral surface of the cerebral
hemisphere. A black and white version of this figure will appear in some
formats. For the color version, please refer to the plate section.
A
Subarachnoid hemorrhage
Subarachnoid bleeding nearly always abruptly increases intra-
cranial pressure (ICP). Systemic blood pressure and volume
must be maintained or augmented to preserve brain perfusion
in the face of the increased ICP. After the initial bleeding, three
major risks affect subsequent events: rebleeding, vasoconstric-
tion, and hydrocephalus. Once the outer wall of abnormal
blood vessels, most often aneurysms and vascular malforma-
tions, has been breached, the vessels are vulnerable to rebleed-
ing. Clearly, a second or third bleed poses substantial threats
for survival because each bleed increases ICP and the amount
of blood in the CSF. Arteries bathed in bloody CSF often
become constricted.135,136 Vasoconstriction can be local or
more diffuse and frequently leads to ischemia, brain edema,
and infarction.136–138 Blood within the CSF can clog the
absorptive membranes, leading to communicating hydroce-
phalus and dilation of all of the ventricular system. At times,
B
the initial bleed or subsequent bleeds are into the brain, as well
as on its surface. In these patients, the discussion of intracer-
Figure 2.48 Drawings of autopsy findings in patients who died of lesions that
ebral hemorrhage also applies because they have both intracer- increased intracranial pressure. (A) A subdural hematoma was present in the
ebral and subarachnoid hemorrhages. region shown by the open arrows. The underlying brain is flattened and
Having presented the basic building blocks for compressed in contrast to the opposite cerebral hemisphere. The extrinsic
pressure on the brain has caused compression of the ipsilateral lateral ventricle
understanding the mechanisms of stroke, we proceed and a shift in midline structures. The increased pressure forced the midbrain
directly to clinical diagnosis at the bedside and then labora- against the contralateral tentorium, causing injury to the contralateral cerebral
tory diagnosis in the following chapters. Subarachnoid hemor- peduncle – “Kernohan’s notch.” (B) A Düret hemorrhage in the midbrain that
developed in a patient with a large intracerebral hemorrhage.
rhage, aneurysms, and vascular malformations are discussed in
Chapter 13.
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54

Pathology Anatomy and Pathophysiology of Stroke

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Chapter

Pathology, anatomy, and pathophysiology

The most common type of vascular pathology is athero-

Figure 2.2 (A) The drawing shows a normal

Figure 2.3 Internal carotid artery atherosclerotic lesions: (A) plaque;

Figure 2.5 Examples of potential sources of embolism: (a) cardiac mural

Figure 2.6 In heart (pump) failure and watershed infarction: (A)

markedly different than arterial ischemia where hemorrhage

also affects treatment: Embolism arising from the heart

Figure 2.11 Drawings of the

Common carotid artery

Ascending pharyngeal Cervical

A-P view Figure 2.12 The intracranial

Anterior cerebral artery

Recurrent artery of Heubner

Internal carotid artery

Posterior cerebral artery

Internal carotid artery

B Anterior choroidal artery

Lateral lenticulostriate arteries

Middle cerebral artery

Posterior cerebral artery Anterior cerebral artery

which unite to form midline arteries that supply the brainstem

Figure 2.17 Drawing of

Choroidal branches from posterior

Figure 2.18 Drawing of a coronal view of the cerebral hemispheres showing

Anterior communicating Figure 2.20 Drawing of a basal view of the brain

Internal carotid artery

Middle cerebral artery

Posterior cerebral artery

Superior cerebellar artery

The intracranial portions of the VAs give off posterior

A-P view Figure 2.21 Large intracranial

Posterior cerebral artery

Superior cerebellar artery

Posterior cerebral artery

Figure 2.22 Drawings of the

ends at the internal occipital protuberance by draining into the

Figure 2.24 Drawing of the arterial “circle” of Willis.

Middle cerebral artery

Anterior choroidal artery

Posterior cerebral artery

Superior sagittal sinus

Figure 2.26 Drawing of a

Inferior sagittal sinus

Superior petrosal sinus

A B Figure 2.27 (A,B) Magnetic

Superior sagittal sinus Figure 2.28 Drawing of major

Middle cerebral vein (Sylvian)

Lesser anastomotic vein (Labbé)

Anterior temporal cerebral vein

Figure 2.29 Drawing of

Posterior thalamic vein

Basilar vein (passing

specific carotid segments is likely determined by flow

Great cerebral Inferior

ICA in the neck, Ringelstein and colleagues separated those

Figure 2.37 Drawings of computed tomography (CT) scans that

Intracerebral hemorrhage Physiology and pathophysiology of brain

These requirements for oxygen and glucose translate into a CBF