Introduction
References Annotated
Bibliography Questions
Pathophysiology of Stroke
Case Presentation
This presentation addresses the pathophysiology
of stroke. The following
topics will be addressed:
1. Conditions that influence ischemic injury
2. Mechanisms of neuron death (coagulation necrosis vs. apoptosis)
3. Cerebral blood flow
4. Survival of brain tissue
5. Features of hypotensive stroke
Pathophysiology of Stroke
Introduction
This brief presentation of pathophysiology
of stroke reviews conditions that influence ischemic injury, mechanisms
of death of neurons (coagulation necrosis vs apoptosis), cerebral
blood flow and survival of brain tissue and features of hypotensive
stroke. Ischemic penumbra and viability of brain tissue, and re-perfusion
hemorrhage - a complication of restoration of cerebral blood flow
to injured brain tissue are also explained.
Understanding of the pathogenesis
of stroke is to understand how ischemia and hemorrhage cause injury.
An ischemic stroke deprives neurons of oxygen and nourishment. Accumulation
of noxious metabolites in the brain tissue originating from the injured
or dying neurons increases with time, which then results in injury
to the surrounding healthy neurons. This process can be halted or
even reversed in the ischemic penumbral brain tissue if restoration
of blood flow occurs within a critical time period.
In hemorrhagic stroke, extra vascular release of blood causes
damage by cutting off connecting pathways, resulting in local or generalized
pressure injury.
Two
major types of “strokes”
cause brain damage: ischemic and hemorrhagic stroke. In ischemic stroke,
which represents about 80% of total strokes, lack of circulating blood
deprives neurons of oxygen and nourishment. The effects are fairly
rapid because the brain does not store glucose and is incapable of
anaerobic metabolism
1
. Hemorrhagic stroke causes damage
to brain tissue by disrupting connecting pathways resulting in local
or generalized tissue injury.
Acute Ischemic Injury
The
occlusion of a major artery such as the middle cerebral artery is
rarely complete and cerebral blood flow (CBF) depends on the degree
of obstruction and the collateral circulation. The vascular compromise
leading to an acute stroke is a dynamic process that evolves over
time and is influenced by many factors
2-5
.
These
conditions influence the progression and the extent of ischemic injury:
(a)
Rate and duration: The
brain better tolerates an ischemic event of short duration than a
prolonged period of ischemia. However, the rate of development of
ischemia also influences the extent of ischemic injury. A slow ischemic
event allows for collateral circulation to be established.
(b)
Collateral circulation:
The impact of ischemic injury is greatly influenced by the
state of collateral circulation in the affected area of the brain.
(c)
Systemic circulation:
Adequate systemic blood pressure is required to maintain cerebral
perfusion.
(d)
Coagulation: Any
hypercoagulable state increases the progression and extent of micro
thrombi, exacerbating vascular occlusion.
(e)
Temperature: Elevated
body temperature is associated with greater ischemic injury
(f)
Glucose: Both
hyper or hypoglycemia have deleterious effects on progression of ischemic
injury.
Pathophysiology at Macro tissue Level
The
normal cerebral blood flow (CBF) is approximately 50 to 60 ml/100gm/minute
and varies in different parts of the brain. In response to ischemia,
the cerebral autoregulatory mechanisms compensate for a reduction
in CBF by local vasodilation, opening the collaterals and increasing
the extraction of oxygen and glucose from the blood. However when
the CBF is reduced to below 20 ml/100gm/minute, an electrical silence
ensues and synaptic activity is greatly diminished in an attempt to
preserve energy stores. CBF of less than 10 ml/100gm/minute results
in irreversible neuronal injury
1;6-11..
Ischemic Penumbra and the Window of Opportunity
Within
an hour of hypoxic-ischemic insult, there is a core of infarction
surrounded by an ischemic zone of oligemia called the ischemic penumbra
(IP) where the auto regulation is ineffective. IP is characterized
by some preservation of energy metabolism since the CBF in this area
is 25% to 50% of the normal. This dynamic zone is also referred to
as the “window of opportunity” since the neurological deficits created
by ischemia can be partly or completely reversed by reperfusing the
ischemic tissue within a critical time period (2 to 4 hours?)
1;6-8;10-12.
Microscopic Mechanisms of Neuronal Injury
Micro-thrombi
form in distal vessels after an occlusion of a major artery such as
the middle cerebral artery. These microvascular occlusions progressively
increase with time
6-10
.
Accumulation of noxious metabolites,
such as lactic acid, glutamate, aspartate etc., originating from injured
neurons increases with time, which results in injuring adjacent healthy
neurons. A destructive cascade becomes established.
Intra-luminal
(endovascular) changes begin with interaction of the endothelial cells
with polymorphonuclear (PMN) leukocytes and platelets that generate
more microvascular occlusions and free radicals, thus exacerbating
neuronal injury
13
. PMN leukocytes play an important role in triggering the cascade
of coagulation necrosis (see below)
14
.
Cellular Mechanisms of Neuronal Injury: Excitotoxicity
At a cellular level, the development of hypoxic-ischemic neuronal injury
is greatly influenced by “overreaction” of certain neurotransmitters,
primarily glutamate and aspartate. This process called “excitotoxicity”
is triggered by depletion of cellular energy stores. Glutamate, which
is normally stored inside the synaptic terminals, is cleared from
the extracellular space by an energy dependent process. The greatly
increased concentration of glutamate in the extracellular space in
a depleted energy state results in the opening of calcium channels.
This causes calcium, sodium, and chloride ions to move into the cells
and potassium to leak out. Intracellular calcium activates a series
of destructive enzymes resulting in the loss of integrity of the cell
membrane, triggering an inflammatory cascade and eventually cell death.
Reperfusion of the infarct site and cellular infiltration may further
exacerbate the inflammatory response
15-19.
Timing of Neuronal Death
The two processes by which the
injured neurons are known to die are coagulation necrosis and apoptosis.
Coagulation
necrosis refers to a process
in which individual cells die among living neighbor cells without
eliciting an inflammatory response. (This is in contrast to liquefaction
necrosis, which occurs when cells die, leaving behind a space filled
by “inflammatory response” or pus.) This type of cell death is attributed
to the effects of physical, chemical or osmotic damage to the plasma
membrane
20
. The cell initially swells then shrinks
and undergoes pyknosis – a term used to describe marked nuclear chromatin
condensation. This process
evolves over 6 to 12 hours. By 24 hours, extensive chromatolysis occurs
resulting in pan-necrosis. Astrocytes then swell and fragment. Myelin
sheaths degenerate causing irreversible injury. The morphology of
dying cells in coagulation necrosis is different than that of cell
death due to apoptosis
10;11;15;17;21
.
The
term Apoptosis is derived from the study of plant life whereby
deciduous trees shed their leaves in the fall. This is also called
“programmed cell death, because the leaves are programmed to die in
response to certain conditions that occur in the fall. Similarly,
cerebral neurons are “programmed” to die under certain conditions,
such as ischemia.
During
apoptosis, nuclear damage occurs first. The integrity of the plasma
and the mitochondrial membrane is maintained until late in the process.
Ischemia activates latent “suicide” proteins in the nuclei, which
starts an autolytic process resulting in cell death. This autolytic
process is mediated by DNA cleavage
22;23
.
Apoptotic mechanisms begin within
1 hour after ischemic injury whereas necrosis begins later – by 6
hours after arterial occlusion. This observation has important bearing
on future direction of research. The manner in which apoptosis evolves
is a focus of much research, since hypothetically, neuronal death
can be prevented by modifying the process of DNA cleavage that seems
to be responsible for apoptosis.
Major Categories of Ischemic Stroke
Ischemic strokes can be grouped
into three main categories: (a) thrombotic, (2) embolic and (3) global
ischemic (hypotensive) stroke. The list of “infrequent” causes is
very long. However, strokes caused by vasospasm (migraine, following
SAH, hypertensive encephalopathy) and some form of “arteritis” stand
out among the more infrequent causes of stroke.
Thrombotic Stroke
Atherosclerosis
is the most common pathological feature of vascular obstruction resulting
in thrombotic stroke
24
. Other pathological etiologies of
vascular occlusion in thrombotic stroke are: clot formation due to
hypercoagulable state, fibromuscular dysplasia, arteritis (Giant cell
and Takayasu), dissection of vessel wall and hemorrhage into a pre-existing
plaque leading to an obstruction of the blood flow.
Embolic Stroke
Most emboli lodge in the middle
cerebral artery distribution because 80% of the blood carried by the
large neck arteries end up in MCA. The two most common sources of
emboli are, the left- sided cardiac chambers and “artery to artery”
emboli – as in detachment of a thrombus from the internal carotid
artery at the site of an ulcerated plaque. Embolic strokes are generally
smaller than thrombotic strokes.
Many embolic strokes become
“hemorrhagic” because ischemic tissue is often reperfused when the
embolus lyses spontaneously and blood flow is restored to a previously
ischemic area.
Global – Ischemic or Hypotensive Stroke
Profound reduction in systemic
blood pressure for any reason is responsible for “hypotensive stroke.”
Cerebral gray matter is particularly vulnerable. Global ischemia causes
greatest damage to areas between the territories of the major cerebral
and cerebellar arteries known as the boundary zone or watershed area.
The parietal-temporal-occipital triangle at the junction of the anterior,
middle and posterior cerebral arteries is most commonly affected.
Watershed infarct in this area causes a clinical syndrome consisting
of paralysis and sensory loss predominantly involving the arm. Face
is not affected and speech is spared.
Selective Vulnerability of Neurons to Global Ischemia
Some neurons are more susceptible to ischemia than others. These include
the pyramidal cell layer of the hippocampus and the Purkinje cell
layer of the cortex. The increased susceptibility is due to an abundance
of the neurotransmitter glutamate found in these neurons, which triggers
the excitotoxicity reaction discussed earlier
21
.
Complications of Restoration of Blood Supply
to a Previously Ischemic Area
Two main complications of restoring
blood supply are hemorrhage and cerebral edema.
An initial vascular obstruction is likely to occur at a bifurcation
of a major vessel. The occlusion may obstruct one or both of the branches,
producing ischemia of the distal tissue. Blood vessels as well as
brain tissue are rendered fragile and injured. When the occluding
embolus either lyses spontaneously or breaks apart and migrates distally,
CBF is restored to the “injured or ischemic” arterioles. This can
result in a hemorrhagic or “red infarct” in what had previously been
a bloodless field. The areas that continue to be poorly perfused are
referred to as “anemic infarcts”
25;26
.
The
following factors are associated with “red infarcts” or a hemorrhagic
transformation of stroke:
(a)
Size of the infarct. The bigger the infarct, the greater the
possibility of hemorrhage.
(b)
Richness of collateral circulation.
(c)
The use of anticoagulants and interventional therapy with thrombolytic
agents is associated with a higher incidence of hemorrhagic transformation.
Vasogenic
edema follows loss of cerebral autoregulatory mechanisms in ischemic
areas of the brain. Large infarcts are associated with a greater potential
of developing cerebral edema. Post ischemic brain edema peaks at 48
to 72 hours after the onset of symptoms
27
.
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Pathophysiology
of Stroke
References
1.
Jones TH, Morawetz RB, Crowell RM, et al: Thresholds
of focal cerebral ischemia in awake monkeys.
Journal of Neurosurgery 1981;54:773-782.
2. Wass CT,
Lanier WL: Glucose modulation of ischemic brain injury: review and
clinical recommendations. [Review] [108 refs].
Mayo Clinic Proceedings 1996;71:801-812.
3. Bruno A,
Biller J, Adams HP, et al: Acute blood glucose level and outcome from
ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST)
Investigators. Neurology
1999;52:280-284.
4. Reith J,
Jorgensen HS, Pedersen PM, et al: Body temperature in acute stroke:
relation to stroke severity, infarct size, mortality, and outcome.
[see comments]. Lancet
1996;347:422-425.
5. Schwab
S, Spranger M, Aschoff A, Steiner T, Hacke W: Brain temperature monitoring
and modulation in patients with severe MCA infarction.
Neurology 1997;48:762-767.
6. Pulsinelli
WA: Ischemic Penumbra in Stroke.
Sci Med 1995;1:16-25.
7. Hakim AM:
Ischemic penumbra: the therapeutic window. [Review] [21 refs].
Neurology 1998;51:S44-S46
8. Astrup
J, Siesjo BK, Symon L: Thresholds in cerebral ischemia - the ischemic
penumbra. Stroke
1981;12:723-725.
9. Zivin JA,
Choi DW: Stroke therapy. Scientific
American 1991;265:56-63.
10.
Wise RJ, Bernardi S, Frackowiak RS, Legg NJ, Jones T: Serial
observations on the pathophysiology of acute stroke. The transition
from ischaemia to infarction as reflected in regional oxygen extraction.
Brain 1983;106:197-222.
11.
Heros RC: Stroke: early pathophysiology and treatment. Summary
of the Fifth Annual Decade of the Brain Symposium. [see comments].
Stroke 1994;25:1877-1881.
12.
Hossmann KA: Viability thresholds and the penumbra of focal
ischemia. [see comments]. [Review] [92 refs].
Annals of Neurology 1994;36:557-565.
13.
Siesjo BK, Agardh CD, Bengtsson F: Free radicals and brain
damage. [Review] [205 refs].
Cerebrovascular & Brain Metabolism Reviews 1989;1:165-211.
14.
del Zoppo GJ, Schmid-Schonbein GW, Mori E, Copeland BR, Chang
CM: Polymorphonuclear leukocytes occlude capillaries following middle
cerebral artery occlusion and reperfusion in baboons.
Stroke 1991;22:1276-1283.
15.
Siesjo BK: Cell damage in the brain: a speculative synthesis.
[Review] [244 refs]. Journal
of Cerebral Blood Flow & Metabolism 1981;1:155-185.
16.
Rothman SMOJW: Excitotoxicity and the NMDA Receptors.
Trends in Neuroscience 1987;10:299-302.
17.
Becker KJ: Inflammation and acute stroke. [Review] [66 refs].
Current Opinion in Neurology 1998;11:45-49.
18.
Hademenos GJ, Massoud TF: Biophysical mechanisms of stroke.
[Review] [45 refs]. Stroke
1997;28:2067-2077.
19.
DeGraba TJ: The role of inflammation after acute stroke: utility
of pursuing anti-adhesion molecule therapy. [Review] [63 refs].
Neurology 1998;51:S62-S68
20.
Kroemer G, Petit P, Zamzami N, Vayssiere JL, Mignotte B: The
biochemistry of programmed cell death. [Review] [84 refs].
FASEB Journal 1995;9:1277-1287.
21.
Garcia JH: Morphology of global cerebral ischemia. [Review]
[52 refs]. Critical
Care Medicine 1988;16:979-987.
22.
Choi DW: Ischemia-induced neuronal apoptosis. [Review] [55
refs]. Current Opinion
in Neurobiology 1996;6:667-672.
23.
Kajstura J, Cheng W, Reiss K, et al: Apoptotic and necrotic
myocyte cell deaths are independent contributing variables of infarct
size in rats. Laboratory
Investigation 1996;74:86-107.
24.
Challa V: Atherosclerosis of the Cervicocranial Arteries,
Philadelphia, Lippincott Williams and Wilkins; 1999:
25.
Lyden PD, Zivin JA: Hemorrhagic transformation after cerebral
ischemia: mechanisms and incidence. [Review] [66 refs].
Cerebrovascular & Brain Metabolism Reviews 1993;5:1-16.
26.
Toni D, Fiorelli M, Bastianello S, et al: Hemorrhagic transformation
of brain infarct: predictability in the first 5 hours from stroke
onset and influence on clinical outcome. [see comments].
Neurology 1996;46:341-345.
27.
Ropper AH, Shafran B: Brain edema after stroke. Clinical syndrome
and intracranial pressure. Archives
of
Neurology 1984;41:26-29.
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Pathophysiology
of Stroke
Questions
1.
Conditions that adversely influence progression and extent
of ischemic injury include all of the following except
a.
systemic hypotension
b.
rapid development of an ischemic event
c.
Hypercoaguable states
d.
Prolonged ischemia
e.
below normal body temperature
f.
Hypo or hyperglycemia
g.
State of collateral circulation
2.
Features of ischemic stroke due to global reduction in cerebral
blood flow (Hypotensive stroke) include all the following except
a.
Hippocampus and purkinje cell layer of the cerebral cortex
are most vulnerable to a reduction in cerebral blood flow
b.
Speech difficulties typify victims of Hypotensive stroke who
recover
c.
Uncontrolled release of excitatory amino acids primarily glutamate
and aspartate cause calcium channels to open up which ultimately leads
to cell death
d.
Sites affected by critically low cerebral blood flow are located
at the end of an arterial territory, the so-called watershed areas
3.
The true statement with regards to ischemic penumbra (IP) is
a.
IP is an area of massive neuronal death that results from a
global reduction in cerebral blood flow (CBF)
b.
CBF in the IP is usually above the 50% of the norm
c.
Auto regulatory mechanisms are preserved in the IP
d.
IP is a potentially salvageable area of marginal blood flow
that surrounds a core of ischemic brain tissue
4.
All of the following are true except
a.
Reperfusion hemorrhage results when ‘fragile’ ischemic or injured
vessels rupture after sudden restoration of blood flow
b.
Hemorrhagic transformation of an ischemic infarct generally
occurs in what had previously been a blood-less field
c.
Hypertensives are more likely to suffer from reperfusion hemorrhage
d.
Thrombolytic therapy increases the likelihood of reperfusion
hemorrhage
Answers
1.
Answer e.
2.
Answer b.
3.
Answer d.
4.
Answer
c.
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