Supplementary material for the stroke lecture

1. Arlyn M. Valencia, M.D.
OUTLINE OF POWERPOINT
PRESENTATION
•Stroke in Perspective
I.Epidemiology
II.Types of Stroke
III.Risk Factors
•Pathogenesis and Pathophysiology
I.Atherosclerosis and Thrombogenesis
II.Cerebral Embolism Formation
III.Effects of Stroke on Brain Function
IV.Cellular Injury During Ischemia
V.The Ischemic Penumbra
•Evaluation and Management
I.Emergent Evaluation and Intervention
II.Clinical Presentations of Acute Stroke
III.Localization
IV.Work-up and Neuroimaging Techniques
V.Emergent Supportive Care and Treatment
VI.Stroke Prevention
IV. Case Studies/ Questions and Answers

2. ATHEROSCLEROSIS AND THROMBOSIS
Atherosclerosis: decades-long process;
progression favored by hypercholesterolemia,
HTN, cigarette smoking
•Fatty streak: yellowish discoloration on
intimal surface of blood vessel;
microscopically, lipid –filled macrophages
called “foam cells” (may be present even in
childhood)
•Focal plaques: eccentric thickening at
bifurcations; addition of massive extracellular
lipids that displaced normal cells and matrix
(late childhood or early
adolescence)
•Complicated fibrous plaques: central
acellular area of lipid covered by a cap of
smooth muscle cells and collagen (third
decade of life); with endothelial injury, caps
thicken quickly as a result of thrombosis-
dependent fibrotic organization

3. ATHEROGENESIS: “RESPONSE TO INJURY”
HYPOTHESIS
Atherosclerosis begins as a response to chronic
minimal injury to the endothelium and interactions
among monocytes, lipoproteins, platelets, lymphocytes,
and smooth muscle cells abet and continue the
pathogenic process
3 TYPES OF VASCULAR INJURY
1. Type I injury: functional alterations of endothelial
cells; primarily caused by
turbulence of blood flow
Other factors: HTN, hypercholesterolemia, circulating
vasoactive amines, immunocomplexes, viral infections,
and a chemical irritant in tobacco smoke
•Type II injury: denuding of endothelium and superficial
intimal injury
accompanied by platelet deposition with or without
thrombus formation
•Type III injury: deep intimal and medial damage with
marked platelet aggregation and mural thrombosis
(usually seen following plaque rupture)

4. ROLE OF MONOCYTES AND T-LYMPHOCYTES
Monocytes bind to endothelium after vascular cell
adhesion molecule (VCAM) is expressed, insinuate
themselves between endothelial cells . Once in the
intima, they are transformed into macrophages and
ingest modified lipids (primarily oxidized lipids).
T lymphocytes help to mobilize macrophages.
OXIDATION OF LDL-CHOLESTEROL
“Scavenger receptor” on macrophages readily
takes up oxidized LDL
Oxidation induced by free radicals produced by
macrophages, endothelial cells, or smooth muscle
cells
Oxidized LDL-cholesterol contribute to
atherogenesis in 3 other ways: 1) its cytotoxic
properties promote endothelial injury; 2) acts as
chemoattractant for monocytes; and 3) inhibits egress
of macrophages from plaques
SMOOTH MUSCLE CELL MIGRATION AND
PROLIFERATION
Makes up substantial bulk of plaque
Factors involved: 1) growth factors (PDGF), 2)
eicosanoids, 3) certain cytokines
(eg, tumor necrosis factor, interleukin-1 and
interferon), and 4) nitric oxide

5. ROLE OF PLATELETS
Contribute to formation of capsule of “fatty lesions”, of
subendothelial “fibrointimal lesions” and stimulate migration
and proliferation of smooth muscle cells
Platelet activation: incited by exposed collagen; activated
platelets acquire enhanced capacity to catalyze interactions
between activated coagulation factors
Platelet adhesion: promoted by damage to intimal surface,
toxic products released by macrophages; platelets adhere to
subendothelial receptors (mainly, GP-Ib-IX)
Platelet aggregation: interplatelet bridging (receptor GP
IIb-IIIa)
THROMBOSIS
Activation of coagulation cascade culminates in generation
of thrombin which converts soluble fibrinogen to fibrin
forming a blood clot. Fibrin molecules aggregate together,
trapping platelets, erythrocytes, and leukocytes
Thrombosis on atherosclerotic plaque may precipitate
acute episodes of transient ischemia and ischemic stroke (as
well as MI and unstable angina)

6. Duration, severity and location of focal cerebral
ischemia determine the severity of brain dysfunction
and thus the severity of stroke.
REQUIREMENT OF CONSTANT ENERGY
SUPPLY
The transient change in voltage induced by the
action potential is determined by the concentration of
ions on either side of cell membrane. Maintaining
these ionic gradients is an energy-consuming process
that requires constant supply of glucose and oxygen to
the neuron.
INADEQUATE ENERGY SUPPLY
Cellular energy stores depleted due to lack of glucose
and oxygen
“Leaky” membrane leads to K+ and ATP loss
5-10 minutes required for irreversible brain damage
One or more branching mechanisms may
independently lead to cell death:
May involve 1) deterioration of ion gradients or
2) effects of anaerobic metabolism

7. DETERIORATION OF ION GRADIENTS
LEADING TO EXCITOTOXICITY
•Anoxic depolarization (equilibrium of intracellular
and intracellular ions) causes potassium exit & sodium,
chloride and calcium entry
•Massive release of glutamate & aspartate
•Glutamate further activates sodium & calcium ion
channels in the neuron membrane ---- cytotoxic edema
•Activation of calcium channels result in furher influx
of calcium
•Entry of calcium through N-methyl-D-aspartate
(NMDA) channel activation: further depletion of
energy, activation of proteases, lipases, and nucleases
•These enzymes & their metabolic products (oxygen
free radicals) cause cell death
•Neuroprotective agents: drugs that would block above
steps; still investigational

8. THE ISCHEMIC PENUMBRA
•Core ischemic zone: blood flow below 10% to
25 %, severe ischemia can result in necrosis of
neurons and glial cells
•Penumbral zone: mild to moderately ischemic
tissue between normally perfused area and the
area in which infarction is evolving; ailing but
salvageable tissue; supplied by collaterals; extent
varies directly with the number and patency of
collateral arteries; if reperfusion not established
in the early hours, cells may die

9. CEREBRAL INFARCTION/ EFFECTS OF
EDEMA
•Edema may cause further damage by compressing
neurons, nerve tracts, and cerebral arteries
•May increase intracranial pressure (ICP) or shift
structures within cranial vault
•Two major types of edema: 1) Cytotoxic: onset
within minutes to hours; swelling of all cellular
elements of the brain (neurons, glia, endothelial cells);
increased intracellular calcium activates
phospholipases and the release of arachidonic acid,
leading to release of free radicals and infarction, 2)
Vasogenic: increase in extracellular fluid volume due
to increased permeability of brain capillary endothelial
cells (onset within hours to days)
ANAEROBIC GLYCOLYTIC PATHWAYS
•Compensate for loss of oxygen & provide source of
energy
Produce damaging byproducts including lactic acid and
hydrogen ions (latter facilitate ferrous-iron-mediated
free radical mechanisms; irreversibly affect neuronal
integrity)