The central nervous system (CNS) consists of neurons and glial

cells.

 Glial cells are astrocytes, oligodendroglia, ependymal cells, and

microglia.
 With H&E stains, the CNS resembles mesenchymal tissues in
which cells are set in an extracellular matrix. This is a wrong
impression.
 The fibrillary "matrix" of the cerebral gray matter,
the neuropil, is formed by the cellular extensions (processes)
of the neurons and glial cells. These processes fit together
tightly, leaving a minimal extracellular space. The neuropil is
traversed by blood vessels.
 As leptomeningeal vessels penetrate the brain, the
subarachnoid space dips into CNS tissue around them, creating
a perivascular (Virchow-Robin) space. This is accentuated
in paraffin-embedded CNS tissue and appears as an empty
space.
 The Virchow-Robin space extends down to the level of arterioles
and venules. In brain capillaries, astrocytes are apposed to the
vessel wall.

Cerebral cortex. H&E stain.

The larger cells are neurons.
The pink substance between
cells is the neuropil. A few
capillaries are also seen.
Neurons

Each neuron has a cell body (the perikaryon), an axon, and

dendrites.

 The dendritic tree is the receptive part of the neuron. The

axon conveys the signal to its target. The cell body contains
the nucleus and most organelles that perform the synthetic and
catabolic activities that keep the neuron and all its parts alive
and functioning.

Neurons come in all sizes.

 Motor neurons, which are the largest cells in the CNS, have a
cell body measuring up to 135 microns.
 Granular neurons of the cerebellum, which are the smallest,
measure 4 microns.

Large neurons have abundant rough endoplasmic reticulum

(RER) which forms aggregates, the Nissl granules. These are easy
to see with cellular stains such as the Nissl stain and H&E.

Spinal motor neuron. Abundant

rough endoplasmic reticulum
(RER) which forms aggregates,
the (blue) Nissl granules
  If the axon is transsected, the RER disaggregates and the
neuronal body balloons. The cytoplasm becomes smooth and
the nucleus is displaced toward the periphery of the cell. This
appearance, which is called central chromatolysis, is a
reversible change that develops during repair of a neuron that
has been disconnected from its target.
Neuron with central
chromatolysis at the left
lower corner. The RER
disaggregates and the
neuronal body balloons.
Three normal neurons
are also seen

Neurons contain numerous mitochondria that are needed for aerobic

energy production. Deficiencies of mitochondrial enzymes affect
primarily the brain and muscle.

- In the brain, mitochondrial disorders cause neuronal loss and

present as encephalopathy, myoclonus, strokes, and other
clinical disorders.

 Anoxic neurons
Hypoxia, ischemia, and hypoglycemia cause irreversible
neuronal injury. Injured neurons shrink, become eosinophilic
due to condensation of mitochondria, and their nuclei become
pyknotic. Such neurons are referred to as anoxic neurons.
 Anoxic neurons.
Injured neurons
shrink, become
eosinophilic due
to condensation
of mitochondria,
and their nuclei
become pyknotic.

Neuronal storage

 Neurons contain numerous lysosomes that are used for life-long

recycling of biomolecules and organelles.

 Deficiency of lysosomal enzymes causes unrecycled substrates

of these enzymes to accumulate in lysosomes. Abnormal
lysosomes gradually fill the cell body and processes, leading to
destruction of neurons. There are many genetically transmitted
lysosomal enzyme deficiencies (neuronal storage diseases).

Cytoskeleton

 The neuronal perikaryon and processes contain longitudinally

arranged 10 nm intermediate filaments (neurofilaments) and
20 to 26 nm tubules (neurotubules). Neurofilament proteins
are chemically distinct from intermediate filament proteins of
other cells.
 Longitudinal section
of axon with
neurofilaments and
neurotubules. The
dark band is myelin.

 Neurotubules are polymers of alpha and beta tubulin. Cross

bridges made up of tau protein and microtubule associated
proteins (MAPs), link neurotubules to one another and anchor
them to other cellular structures.

 The neurotubules and neurofilaments form a lattice

(or cytoskeleton) which supports the structure of the axon
and regulates axonal transport.

 Phoshorylation of neurofilamnets influences the structural

stability of axons and speed of axoplasmic flow.

 In Alzheimer's disease, abnormal filaments (paired helical

filaments) appear in the perikaryon, forming neurofibrillary
tangles (NFTs).
The most important parts of the neuronal membrane are the
synapses. Most synapses develop on thorn like processes of
dendrites, the dendritic spines.

 Each synapse consists of the presynaptic process (axon

terminal), the synaptic cleft, and the postsynaptic process (part
of a dendrite).
 The axon terminal contains neurotransmitters packaged in
synaptic vesicles. The membrane of these vesicles contains
special proteins, including synaptophysin and synapsins.
 Upon excitation, the synaptic vesicles fuse with the synaptic
membrane and discharge their contents into the synaptic cleft.
 Contact of neurotransmitters with receptors on the postsynaptic
membrane elicits cellular reactions that transmit the message
to the postsynaptic neuron. The most important excitatory
neurotransmitter is glutamate and the most important inhibitory
neurotransmitter is gamma amino butyric acid (GABA).

Staining of neuronal processes

The Hematoxylin and Eosin (H&E) stain is adequate for routine study
of cellular details of neurons and glial cells, but does not stain the
neuronal processes.

 Axons and dendrites are demonstrated best with silver stains in

which ammoniacal silver is deposited on cytoskeletal
components and then reduced to black metallic silver.

 The most commonly used silver stain is the Bielschowsky

stain, which shows normal axons and dendrites and reveals
also the lesions of Alzheimer's disease.
  Specific chemical components of nerve cells such as
cytoskeletal proteins and synaptophysin, can be demonstrated
by immunohistochemical methods.

Axons and dendrites as seen with

the Bielschowsky stain.

Synaptophysin immunostain
outlines the inferior olive.

The generic term "degeneration" in reference to the cortex or other

neuronal systems (e.g. striatonigral degeneration, cerebellar
degeneration) means gradual neuronal atrophy leading to neuronal
loss. Such a process characterizes most "neurodegenerative"
diseases. In some of these diseases, such as Alzheimer's
disease and Parkinson's disease, there are also specific
histopathologic changes. In others, there is only neuronal loss, brain
atrophy, and gliosis.

The term "neuronal plasticity" (meaning originally the ability to

mold, change shape) refers to change or adaptation of neuronal
function and structure dependent on activity. A clinical example of
plasticity is resumption of a function, e.g. speaking or control of
swallowing, by another group of neurons when the neurons that
originally performed this function are lost due to a stroke. The best
known laboratory example of plasticity is long term potentiation.
The neuronal structure, especially the density of dendritic spines,
changes as a result of neuronal activity. Neuronal plasticity is the
basis of learning.
Astrocytes

Astrocytic processes. GFAP immunostain. This

picture explains why these cells are called star
cells.

Astrocytic processes wrapping around a brain

capillary. GFAP immunostain.

 Astrocytes (star cells) have radially arranged processes.

 Their cytoplasm contains intermediate filaments composed of a

distinct protein, glial fibrillary acidic protein(GFAP),
encoded by a gene on 17q21. GFAP is also found in
nonmyelinating Schwann cells and glial cells of the enteric
nervous system.

 Antibodies against this protein are routinely used to

demonstrate reactive and neoplastic astrocytes. Historically,
GFAP was the first immunostain to be used.
Radial glia

 During brain development, astrocytic processes (radial glia)

guide neurons in their migration from the wall of the ventricles
to the cortex.
 Radial glia are also a source of neuronal and astrocytic stem
cells in the developing brain.

Glia limitans

Brain capillary. A:astrocytic processes;

E:endothelium; Arrowheads:vasular basement
membrane.
‘’GFAP FORMS THE STRUCTURE AND SUPPORT OF
ASTROCYTES WHICH FORM THE INFRASTRUCTURE OF BRAIN
ON WHICH OTHER CELLS AND VESSELS OF BRAIN ARE
ANCHORED’’

 GFAP is a structural protein that maintains the shape and

supports the mechanical strength of astrocytes.

 In the mature brain, there are 5 to 10 times as many astrocytes

as there are neurons. The network of astrocytic processes forms
the infrastructure on which all other CNS cells and vessels are
anchored.

 Astrocytic processes are intertwined with neurons, axons, and

myelin; they cover dendrites and synapses; they surround brain
capillaries; interdigitating astrocytic processes form a thick
layer on the surface of the CNS, the glia limitans. This layer
seals the surface of the CNS and dips into brain tissue along
the perivascular (Virchow-Robin) spaces.

Astrocytic foot processes surround brain capillaries and, during

development, induce endothelial cells to form tight junctions.

The endothelial tight junctions are the basis of the blood-brain

barrier, a system of controlled transcapillary transport which
maintains homeostasis in the CNS. Endothelial tight junctions are
found only in brain capillaries.
 1. Loss of the integrity of the endothelial barrier causes fluid to
leak into the interstitial space, leading to vasogenic
cerebral edema. This raises intracranial pressure and can
collapse brain capillaries, resulting in arrest of cerebral
perfusion.

2. Cerebral edema is caused by a variety of pathological

processes, including ischemic insults, inflammation, and
malignant brain tumors whose capillaries do not have tight
junctions.
3. Astrocytes are less vulnerable than neurons to ischemic
injury but they are damaged if there is lactic acidosis. Such
damage causes intracellular fluid accumulation (cytotoxic
edema).
4. Cytotoxic edema involves the cerebral cortex, whereas
vasogenic edema is more pronounced in the white matter.
Vasogenic edema is more important clinically than cytotoxic
edema.

POTASSIUM BALANCE IN EXTRACELLULAR FLUID

Through their extensive contacts and interactions with neurons and

vessels astrocytes play a very important role in the function of the
CNS in addition to providing structural support. They take up K+
that is released during neuronal activity thus maintaining ion
balance in the extracellular fluid.
GLYCOGEN IN ASTROCYTES

The small amount of glycogen that is present in astrocytes is the

only form of stored energy in the CNS and can be used when
neuronal activity demands it. More important, the coupling of
astrocytes to synapses and vessels facilitates the entry of glucose
into the CNS in response to neuronal activity.

NEUROTRANSMITTER UPTAKE AND RECYCLING

They take up and recycle GABA and glutamate that are released
at synaptic clefts.

Glutamate is converted to glutamine by glutamine synthetase.

Glutamine is then released into the extracellular space, taken up by
neurons, and converted to glutamate by glutaminase.

Astrocytes also produce new glutamate from glucose via the

tricarboxylic acid cycle. This replenishes glutamate lost through
oxidative degradation. Without astrocytes, neurons would not have
their most important neurotransmitter.

In addition, astrocytes influence synaptic activity by releasing

glutamate directly into the extracellular space.
Reactive (gemistocytic) astrocytes around a
cerebral infarct. These cells form scar tissue in
the CNS.

Reactive astrocytes-GFAP

ASTROGLIOSIS

 When neurons are lost and brain tissue is damaged from

whatever cause, astrocytes proliferate, fill the gaps, and restore
CSF-brain and blood-brain barriers. This process, which is
called astrogliosis or plain gliosis, involves proliferation and
hypertrophy of astrocytes, and is for the CNS what scarring is
for extraneural tissues.

 Moreover, in addition to gliosis, astrocytes participate in

inflammatory and degenerative processes by secreting
cytokines and assuming various other functions. Some of these
functions are neuroprotective and others may be detrimental.
 Astrocytes participating in gliosis are referred to as reactive
astrocytes. They have a large cytoplasmic mass, long,
branching processes, and increased cytoplasmic filaments. Such
astrocytes are also known as gemistocytic astrocytes from a
Greek word that means to fill up.

 Hepatic failure and other situations associated with high blood

ammonia such as porto-systemic shunts precipitate the
syndrome of hepatic encephalopathy, characterized by
confusion, drowsiness, stupor or coma.

Alzheimer type II astrocytes in

hepatic encephalopathy. In acute
metabolic disorders such as hepatic
encephalopathy, hyperammonemia,
and cerebral ischemia, astrocytes
enlarge. Their nuclei are large and
appear clear in H&E stains.

Ammonia taken up by astrocytes is converted to osmotically

active glutamine, which causes cytotoxic astrocytic swelling. In
addition to the rise in intracranial pressure, this process
compromises astrocytic function.

Swollen astrocytes in hepatic encephalopathy are

called Alzheimer type II astrocytes. Their nuclei are large and
appear clear in H&E stains. A similar change develops in
hypoxia-ischemia.

NEUROMYELITIS OPTICA

Aquaporin4 (AQP4), the most abundant water channel in the

CNS, is located in astrocytic membranes facing the blood-brain
and brain-CSF interfaces.

In neuromyelitis optica (NMO), IgG autoantibodies elicit an

inflammatory reaction that destroys AQP4, leading to disruption
of the blood-brain barrier, oligodendrocyte loss, and
demyelination.
Rosenthal fibers (RFs) are homogeneous, eosinophilic, elongated,
or globular inclusions in astrocytic processes. They have a
filamentous and granular structure and contain GFAP. They are seen
in old brain scars dating back to childhood, and in some low-grade
astrocytomas. Mutations of GFAP cause Alexander
disease,characterized by diffuse deposition of RFs, resulting in
white matter degeneration and neurological dysfunction. The RFs in
Alexander disease contain mutant GFAP and other proteins.

Rosenthal fibers.
Homogeneous,
eosinophilic, elongated or
globular inclusions in
astrocytic processes.
Corpora amylacea are spherical intracytoplasmic bodies of
carbohydrate polymers that develop in astrocytic processes with
advancing age. They have no pathological significance. The
astrocyte is the cell in the adult mammalian brain most capable of
undergoing mitosis. Most brain tumors are derived from astrocytes
(astrocytomas).

Corpora amylacea.
Spherical
intracytoplasmic bodies
of carbohydrate
polymers that develop in
astrocytic processes.
Oligodendroglia
 Myelin is a sheath of plasma membrane wrapped around an
axon. Its insulating properties are important for conductivity. It
consists of 70-80% lipids and 20% structural proteins, including
Proteolipid Protein, Myelin Basic Protein and Myelin Associated
Glycoprotein.

Myelin. The dark ring consists

of layers of oligodendroglial cell
membrane wrapped around the
axon.

 In the CNS, myelin is made by oligodendroglial cells; in

peripheral nerves by Schwann cells. Each Schwann cell makes
one segment of myelin; each oligodendrocyte makes multiple
segments of myelin that wrap around several axons.

Oligodendroglial cell supplying

myelin for several axons.
  Oligodendroglial cells are present in gray matter and in white
matter. In paraffin sections, oligodendroglial cells have clear
cytoplasm, an appearance referred to as "fried egg". This is an
artefact of histological processing and is replicated in tumors of
oligodendroglial cells.

Oligodendroglial cells in white

matter. Note the clear
cytoplasm.

Most myelin stains use hematoxylin-based solutions that attach to

phospholipid components of the myelin sheath and give myelin a
deep blue color.
MYELIN AND OLIGODENDROCYTES ARE MORE SENSITIVE TO
HPOXIA AND ISCHEMIA

Myelin and oligodendrocytes are non-specifically lost in cerebral

infarcts, infections, and other lesions that involve the white matter.
They are especially sensitive to hypoxia and ischemia in premature
infants.

 Oligodendrocyte injury in the perinatal period can cause white

matter infarcts or permanent white matter loss around the
lateral ventricles (periventricular leukomalacia).

 Oligodendrocyte loss occurs also in demyelinative disorders,

such as multiple sclerosis and progressive multifocal
leukoencephalopathy (PML).

 PML is caused by a papovavirus infection of oligodendrocytes.

Myelin proteins are immunogenic, and some aspects of
 inflammatory demyelinative disorders are due to
autoimmunity.

 Leukodystrophies are metabolic disorders caused by

biochemical abnormalities of myelin lipids and proteins. They
show diffuse and progressive loss of myelin. The term
"degeneration" in reference to myelin means loss of myelin; in
reference to the white matter or specific tracts (e.g. posterior
colum degeneration), it means loss of myelin and axons.

Oligodendrocyte precursor cells (OPCs)

 In addition to myelinating oligodendrocytes, the mature brain

contains a large number of oligodendrocyte precursor
cells (OPCs), that can be distinguised by specific markers they
express.

 OPCs are generated in fetal life and postnatally; they do not

make myelin but retain their undifferentiated stem cell status.
The potential of OPCs to differentiate and repair multiple
sclerosis and other demyelinating disease lesions remains to be
explored.
Ependyma
The ependymal cells line the walls of the ventricles and form the
specialized choroid plexus epithelium which secretes the
cerebrospinal fluid (CSF).

The ependymal lining may be injured and lost as a result of

infections involving the cerebral ventricles (ventriculitis) and
intraventricular hemorrhage.

Residual ependymal cells proliferate and form tubules (rosettes)

and small nodules with admixed reactive astrocytes (ependymal
granulations) in the walls of the ventricles.
Lymphocytes, Monocytes-Macrophages, And
Microglia
The brain contains very few lymphocytes compared to other organs
that do not have a vascular-tissue barrier. However, even in
absence of pathology, a few T-lymphocytes regularly cross the
intact blood brain barrier, wander in brain tissue for short distances,
and re-enter the circulation.

Activation of T-lymphocytes as a result of nonspecific infections

greatly enhances their ability to randomly cross the blood-brain
barrier. Recognition of antigens in CNS parenchyma results in
retention and recruitment of T-lymphocytes, leading to
inflammation.

B-lymphocytes probably also randomly traffic through the brain in

a similar fashion and, if they find specific antigens, they aggregate
and produce IgG antibodies.

The brain contains two sets of monocyte-macrophage

cells, parenchymal microglial cells and blood-borne
monocytes.

Parenchymal microglial cells

 The parenchymal microglial cells are mesodermally derived cells

which enter the brain early in gestation.
 They comprise approximately 12% of cells in the brain and are
more abundant in gray matter.
 Their first function is to phagocytose neurons that undergo
programmed death during development.

 In the mature brain, they are a very stable and long-lived cell
population and are replenished from bone marrow cells at a
very low rate. In their resting form, they are inconspicuous.
They have elongated nuclei and a small amount of cytoplasm
with short processes.

 Microglial cells have receptors that enable them to sense

damaged tissue and to recognize viruses, environmental and
endogenous toxins, and other pathogens. Such recognition
leads to upregulation (activation) of microglial cells.

 Activated microglial cells have large rod-shaped nuclei and

greatly ramified cytoplasm. They encircle degenerating neurons
(neuronophagia) and form clusters around small foci of
necrotic brain tissue (microglial nodules).

 They can also transform into brain macrophages. Activated

microglial cells produce trophic factors that are important for
neuronal recovery but also make cytokines and neurotoxins
such as NO and glutamate that mediate neuroinflammation and
can kill neurons.

 Microglial cells are important for monitoring the CNS

environment and restoring homeostasis after CNS injury.
However, persistent activation of microglia has damaging
effects and is thought to contribute to the neurodegeneration
that occurs in Alzheimer's disease, Parkinson's disease, HIV
 encephalopathy, and other conditions. Microglial activation also
develops progressively with advancing age in absence of
stimulation.

Macrophages

Blood-borne monocytes

Blood-borne monocytes are located in the perivascular spaces, the

leptomeninges, and the choroid plexus.

 The most important of these cells are the perivascular

monocytes which reside just outside the vascular basement
membrane.
 These cells are the main antigen-presenting cells of the CNS,
thus playing an important role in immune reactions involving
the brain. Their location at the interface between brain
parenchyma and the vascular system and their continuous
circulation in and out of blood vessels suits them ideally for this
 function. They along with CD4 lymphocytes are also the main
cells that bring HIV into the brain.
 Perivascular monocytes can also transform into macrophages.
The earliest macrophages following brain injury arise from
parenchymal microglia. After a few days, most macrophages
arise from perivascular monocytes. Regardless of their
derivation, macrophages are large amoeboid cells with a
foamy or granular cytoplasm, full of lipid and other products
they have ingested.

Tissue Patterns
Neurons and glial cells are arranged in varying patterns in different
parts of the CNS.

In the cerebrum and cerebellum, the cell bodies and dendrites of

neurons are on the surface (cerebral cortex: shell) and their
myelinated axons (white matter) in the internal part of the
hemispheres. The spinal cord has the opposite design: the neuronal
cell bodies (anterior and posterior horns) are in the center and the
white matter at the periphery. The white matter of the cerebral
hemispheres and spinal cord consists of myelin, oligodendroglia,
astrocytes, microglia, and blood vessels. It contains no neurons. The
central portion of the cerebral hemispheres (basal ganglia -
diencephalon) and the brainstem contain several masses of neurons
(nuclei) that are intimately mixed with white matter.
In most of the cerebral cortex (neocortex), neurons are arranged in
five layers with a sixth layer consisting of synapses on the surface.
These five layers contain mainly two types of neurons,

 pyramidal cells (large neurons with an apical dendrite and a

long axon) and
 stellate or granule cells (smaller neurons with many
dendrites and short axons).

Pyramidal cells project their axons to targets away from their

points of origin. Stellate cells receive afferents and form
intracortical networks.

Pyramidal cells are found in layers 3, 5, and 6 and stellate cells

mainly in layers 2 and 4.

The mix of pyramidal and stellate cells varies in different cortical

fields and correlates with cortical function.
 The hippocampus

The hippocampus

In the medial edge of the temporal lobes, the neuronal layers are
reduced to two, the pyramidal and the granular (or dentate gyrus).

These layers are wound around one another and form a structure
that is called hippocampus (sea horse, literally caterpillar horse),
because of its peculiar structure. The two neuronal layers can be
best appreciated in coronal sections.

The term Ammon's horn, used also for the hippocampus, describes
its longitudinal shape, parallel to the temporal lobe. The subiculum
and entorhinal cortex are located between the hippocampus and the
temporal neocortex. The hippocampus receives extensive afferents
from association cortex and limbic areas, and projects to the
thalamus, hypothalamus, and cortex. It is especially important for
the process of episodic memory, i.e. the memory for personally
experienced events. Its role in semantic memory (memory for facts)
is not clear and it is not a storage depot for old memories. These are
stored at multiple sites in the neocortex.

Bilateral lesions of the hippocampus (and medial dorsal nucleus of

the thalamus) cause Korsakoff's amnesia, a disorder
characterized by inability to remember new things with relative
preservation of established memories.
CHAPTER 2
CEREBRAL ISCHEMIA AND STROKE

Hypoxic - Ischemic Encephalopathy. General

Principles

The brain is about 2% of the total body mass but consumes 15% of
the energy generated in the body.

 Most of this energy is used by neurons to maintain resting

potentials and restore ionic concentrations after synaptic
transmission.

 Some energy is also used to support synthetic and catabolic

activity of neurons and glial cells and, in young age, for growth.
Energy for these functions is derived from hydrolysis of ATP.
Thus, the brain is like a chemical battery of ATP which must be
constantly recharged.

ENERGY BACK UP FOR BRAIN

 Brain cells have no back up energy source such as creatine

phosphate. The brain has no energy stores of its own except for
a small amount of glycogen in astrocytes. Anaerobic glycolysis
of this glycogen provides neurons with some lactate that can be
used by mitochondria but is insufficient to meet energy needs.
The brain can also use lactate from the circulation.
  Fatty acids cannot be used because they are not transported
across brain capillaries, but the brain can use ketone bodies
derived from fat.

 In the ketogenic diet that is used for treatment of drug-

resistant epilepsy, ketone bodies become the main energy
source.

 However, the bulk of ATP is derived from oxidative

phosphorylation of glucose. Thus, the brain depends on a
second by second supply of oxygen and glucose by the blood. A
drop in cerebral perfusion, hypoxia, hypoglycemia, and
severe anemia can cause a critical shortage of energy
(energy crisis).

 In protracted generalized seizures, neurons use up glucose

and oxygen faster than they are supplied, and discharge
glutamate (see below) with the same result.

The most common cause of energy crisis is a drop

of cerebral perfusion (global ischemia), usually resulting from
cardiac arrest or severe hypotension (shock). Sustained severe
hypoglycemia, and seizures lasting 1-2 hours also cause permanent
brain damage.

Pure hypoxia in clinical settings is unusual. Patients with lung

disease are treated with oxygen and the brain can adapt to
pure hypoxia, especially if it develops slowly.
Hypoxia develops acutely in CO poisoning, which displaces oxygen
from hemoglobin.

Global ischemia is worse than hypoxia, hypoglycemia, and seizures

because, in addition to causing energy failure, it results in
accumulation of lactic acid and other toxic metabolites that are
normally removed by the circulation.

The mechanism of neuronal damage in hypoxic-

ischemic encephalopathy (HIE) is now beginning to be understood.
Obviously, lack of energy causes initially electrical failure and, if it
lasts long enough, results in arrest of cellular functions and cell
death. However, animal experiments and clinical studies show that
there are other factors, in addition to energy loss, that account for
neuronal damage. Even sublethal HIE can set in motion a series of
toxic reactions that finish off injured neurons and kill additional ones
that have not been damaged during the initial insult. Thus, following
global ischemia, neurons do not die suddenly or all at once. In some
of them, damage develops hours or days after the insult. Most
neurons undergo necrosis. In some neurons, HIE triggers apoptosis.
The first result of energy depletion is failure of Na+ and K+ pumps,
leading to depolarization of the neuronal membrane (see diagram
on left). Synaptic function and conductivity cease at this point.

Depolarization causes neurons to release glutamate into the

synaptic cleft. Glutamate is the most common excitatory
neurotransmitter. In small amounts, it is indispensable for neuronal
function. In excessive amounts, it is a neuronal poison, a toxin, and
has been called excitotoxin. Some glutamate receptors are non-
selective cation-permeable ion channels. Initially, over-activation of
these channels causes a passive influx of Cl- (and Na+) into cells
causing osmotic (cytotoxic) edema and rapid death. Additional
structural damage develops hours or days later as a result
of Ca++ influx into neurons. The NMDA and AMPA receptors of
glutamate are channels that are permeable to Ca++. Activation of
these receptors by excess glutamate causes massive influx of
Ca++ into neurons. Ca++ activates catabolic enzymes (proteases,
phospholipases, endonucleases). Ca++ also activates NO synthase,
resulting in formation of the free radicalNO. Additional free radicals
result from the impairment of oxidative phosphorylation. Free
radicals and activated catabolic enzymes destroy structural proteins,
membrane lipids, nucleic acids, and other cellular contents, causing
neuronal necrosis. DNA damage from endonucleases and
mitochondrial injury from free radicals trigger apoptosis.

Counteracting the action of glutamate is the basis of neuroprotective

strategies that are now at an experimental stage.
LACTIC ACIDOSIS

Incomplete combustion of glucose results in lactic acidosis. Lactic

acid can get through cell membranes and can damage not only
neurons but glial and mesenchymal cells as well.

Additionally, lactic acid and hydrogen ions cause cerebral edema by

attracting water. Obviously, lactic acidosis is more severe in
patients with HIE who are hyperglycemic and is not a
significant factor in hypoglycemic encephalopathy or seizures.

Severe HIE is accompanied by cerebral edema and its effects are

compounded by increased intracranial pressure. Cytotoxic
(intracellular) edema develops in the initial phase of the
insult. Interstitial cerebral edema, which follows, is due to
vascular injury and the release in the interstitial space of vasoactive
metabolites such as arachidonic and other fatty acids (derived from
membrane glycerolipids), lactic acid, electrolytes and other unknown
osmoles. Arachidonic acid also has a chemotactic function and
induces acute inflammation.

REPERFUSION

 Free radicals, lactic acid, cerebral edema, and inflammation

cannot develop in unperfused, completely ischemic tissue. They
develop following reperfusion. In an ironic sense, the brain
has to be alive in order for the changes of neuronal death to
develop. Thus, reperfusion is a double-edged sword. Without it,
there is no hope for recovery. On the other hand, reperfusion
causes additional (delayed) neuronal injury, brings monocytes
 to the site of injury, and sustains the glial and vascular
reactions that follow. Knowledge of the various aspects of HIE
and reperfusion injury may open the way to possible
neuroprotective interventions.

THE PATHOLOGY OF HYPOXIC-

ISCHEMIC ENCEPHALOPATHY

Anoxic neurons Neuronophagia

 With this background, let us examine what happens with

different grades of HIE. Suppose that someone has a brief
episode of global ischemia, say from fainting. Within seconds,
energy failure causes electrical activity in neurons to cease and
the patient loses consciousness. Neurons and glial cells are
 viable and, if circulation is promptly restored, the patient
returns to normal.

 If, however, ischemia lasts longer, first the integrity of cell

membranes will be compromised and then cellular metabolism
will cease and neurons will die.

 Ischemia lasting 4-5 minutes can damage irreversibly

hippocampal and neocortical pyramidal cells, striatal neurons,
and Purkinje cells. More protracted ischemia can damage
thalamic and brainstem neurons.

If a patient dies shortly after the insult, the brain is usually grossly
and microscopically normal. If the patient survives and perfusion is
restored, changes begin to appear within hours. At first, injured
neurons shrink and become eosinophilic. This is due to increased
density of damaged mitochondria. Neuronal nuclei condense. The
shrunken eosinophilic neuron (anoxic neuron) is the hallmark of
HIE. Astrocytes swell (Alzheimer type II cells). This is a poorly
understood response of astrocytes to metabolic insults. If the
patient survives longer, damaged neurons disintegrate and are
removed by macrophages. With time, cortical atrophy and
gliosis develop.

Some cases of HIE, usually after brief insults, cause neuronal death
only without damage of glial cells (selective neuronal necrosis).

Neurons are more sensitive than glial cells because they have higher
energy demands and only they produce glutamate. Some neurons
are more vulnerable than others (selective vulnerability). The
hippocampal pyramidal cells of CA1, pyramidal neocortical neurons
(layers 3, 5, and 6), Purkinje cells, and striatal neurons have the
highest vulnerability.

Hippocampal neuronal loss

(right) post-HIE

Pseudolaminar necrosis

Pseudolaminar necrosis

Damage of the cortex sometimes causes a band-like lesion,

called pseudolaminar necrosis.

There is also a regional variation in susceptibilityto HIE.

The cerebral cortex and striatum are more sensitive than the
thalamus, and the thalamus in turn is more sensitive than the
brainstem.

The spinal cord may remain uninjured even when all the rest of the
CNS is severely damaged. The most likely explanation for this
selective vulnerability is that susceptible neurons produce more
glutamate. In severe cases of HIE, not only neurons but glial cells
are damaged as well.

The key factor that converts selective neuronal necrosis to total

tissue necrosis is probably lactic acidosis.

Hippocampal sclerosis, left

Hippocampal sclerosis

The term HIE encompasses hypoxia, ischemia, hypoglycemia, and

the efects of prolonged seizures. Shock and cardiac arrest develop
at some point in most severe HIE cases, and the neuropathology is
the same regardless of the initial event.
  Only rarely it is possible to identify the cause of HIE based on
the pathological findings. For instance, bilateral hippocampal
neuronal loss and gliosis (hippocampal sclerosis) without
other lesions is seen in some patients with epilepsy or following
cardiac arrest of short duration.

 Sparing of Purkinje cells suggests hypoglycemic encephalopathy

but is also seen in HIE without hypoglycemia.

 In addition to causing hypoxia, CO binds to iron-rich neurons of

the globus pallidus and substantia nigra, damaging these nuclei
selectively.

Non-perfused brain

"Respirator brain"
  Severe and protracted HIE damages the cortex, deep nuclei,
and brainstem, resulting in brain death. If such a patient is
put on the respirator, the brain (under normal body
temperature) undergoes an enzymatic autodigestion which may
end in liquefaction. The term"respirator brain" that has been
applied in such cases is misleading because the autolysis is not
caused by the respirator. The term "non-perfused brain" is
more accurate. Because circulation is arrested and all metabolic
activity ceases, the non-perfused brain does not show any
reactive changes (inflammation, macrophages, gliosis), only
autolysis. Imaging reveals hypodensity due to edema and
disintegration of brain tissue without enhancement.

In some instances, global ischemia causes bilateral, symmetric

cerebral infarcts in the border zones between major arterial
territories. Rarely, HIE involves the white matter, causing myelin
damage and loss. Unravelling of damaged myelin results in
vacuolization and a spongy appearance of the white matter in tissue
sections. White matter damage is common in CO poisoning but may
occur in other forms of HIE.
THE CLINICAL CONSEQUENCES OF HYPOXIC-
ISCHEMIC ENCEPHALOPATHY
The most common pattern of injury in HIE is selective loss of
sensitive neurons (pyramidal cells of CA1 of the hippocampus,
layers 3, 5, and 6 of the neocortex, Purkinje cells, and striatal
neurons).

Mild HIE, such as a brief cardiac arrest, may affect CA1 pyramidal
neurons of the hippocampus only.

Bilateral hippocampal damage causes Korsakoff's

amnesia. This is a memory disorder characterized by inability to
retain new information (anterograde amnesia) and a less severe
defect of recall of old memories (retrograde amnesia).

Hippocampal amnesia (Korsakiff's amnesia) affects more severely

episodic memory and less so semantic memory (see below)

MEMORY
PROCEDURAL: Learning skills (learning how), e.g., how to write
with the left hand, if right -handed.
DECLARATIVE: two types
SEMANTIC: Memory for facts (learning that), e.g., Kabul is the
capital of Afghanistan. EPISODIC: Memory for personally
experienced events, e.g., remembering where you parked your car
this morning.
Diffuse cortical, thalamic, or combined neuronal loss (with intact
brainstem) results in dementia or the persistent vegetative
state(loss of cognitive functions and emotion with preservation of
sleep-wake cycles, autonomic function, and breathing). The medical,
legal, and ethical issues revolving around the persistent vegetative
state were dramatized in 2005 by the case of Terri Schiavo.

More protracted ischemic insults, which damage also the brainstem,

cause brain death, a terminal clinical state characterized by loss
of cerebral and brainstem function.

The clinical criteria for brain death are complete unresponsiveness,

absence of brain stem reflexes, electrical silence (flat EEG), and
absence of cerebral perfusion. The latter is probably due to blockage
of capillaries from endothelial swelling and cerebral edema. Brain
death can be distinguished clinicallly from the persistent vegetative
state and other conditions that cause severe brain damage and
coma. In most cases, brain death leads to loss of vital functions.
Therefore, for legal purposes, brain death is the equivalent of
somatic or cardiorespiratory death.

THE WHITE MATTER IN HIE

 Gray matter uses 2.5 times more ATP than white matter, and,
for this reason, HIE damages primarily the cerebral cortex and
deep nuclei.

 The white matter is only rarely affected. One exception is CO

poisoning, in which the white matter is affected, along with
but sometimes out of proportion to the pathology in the cortex
and basal ganglia.
 In addition, the white matter, especially in subcortical regions,
is involved diffusely in chronic ischemia, leading to a condition
called leukoaraiosis. Leukoaraiosis (rarefaction of the white
matter) is a neuroradiology term describing the loss of density
of the white matter on CT and increased signal on T2 or FLAIR
MRI. These findings can be explained by loss of myelin and
axons and increased interstitial fluid. Leukoaraiosis is probably
due to the chronic effect of microvascular disease associated
with hypertension, diabetes, and angiopathies (cerebral amyloid
angiopathy, CADASIL, Collagen 4A1 mutation-see page
2 and page 3 further on). Some of these angiopathies also
cause intracerebral hemorrhage. Its most common substrate is
small vessel disease and patients with leukoaraiosis frequently
also have lacunar infarcts. The extent of white matter pathology
can be best appreciated by MRI, especially with newer
techniques such as diffusion tensor imaging, which measures
the density of axons traversing the white matter. Pathological
examination reveals loss of myelin and axons and expansion of
perivascular spaces, a finding known in classical neuropathology
as état criblé (a sieve-like state).

 Binswanger encephalopathy, a white matter degeneration

that has been linked to hypertension, is a pathological
counterpart of some cases of leukoaraiosis.

 The pathogenesis of leukoaraiosis is unknown and probably has

to do with nonspecific axon and myelin damage due to
chronic ischemia. In that sense it may be considered as being
analogous to periventricular leukomalacia (PVL), however, the
term PVL should be restricted to the neonatal condition. –
 Leukoaraiosis and the conditions that cause it are is associated
with cognitive decline and dementia, instability and gait
abnormality with frequent falls, and bladder dysfunction.
CEREBRAL INFARCTS
Cerebral infarction is focal brain necrosis due to complete
and prolonged ischemia that affects all tissue elements,
neurons, glia, and vessels.

CLINICAL FINDINGS
Ischemic infarcts cause focal neurological deficits. In embolic
infarcts, these appear abruptly. In atherothrombotic infarcts, they
evolve over a period of time, usually hours. Atherothombotic infarcts
are often preceded by transient ischemic attacks (TIAs). A TIA is
a focal neurological deficit that lasts less than 24 hours and
resolves.

The mechanism of TIAs is uncertain. They may be caused by critical

reduction of perfusion that impairs neurological function but falls
short of causing permanent tissue damage, or by emboli that break
up soon after they occlude vessels.

The release of osmotically active substances (arachidonic acid,

electrolytes, lactic acid) from the necrotic brain tissue
causes cerebral edema.

This is aggravated by vascular injury and leakage of proteins in the

interstitial space. By 3-4 days, interstitial fluid accumulates in the
infarct and around it. This is the most dangerous period for a
large cerebral infarct. Death from a massive hemispheric infarct is
caused by cerebral edema and herniations, not by the loss of brain
tissue.
Recovery of function, after an infarct, is due initially to restoration of
perfusion in the penumbra (see below) and then to settling down of
cerebral edema. Additional improvement may occur later through
mechanisms involving neuronal plasticity.

ISCHEMIC PENUMBRA

The basic mechanisms of cell and tissue injury that were discussed
under HIE apply also to infarcts. One additional concept,
the ischemic penumbra, is worth stressing.

 In every infarct, there is a central core of total ischemia and

necrosis which is irreversible. This area is surrounded by a zone
of borderline ischemic tissue, the ischemic penumbra. Ischemia,
in the penumbra, causes dysfunction due to ionic and metabolic
dysfunction but is not severe enough to result in structural
damage.

 Prompt restoration of perfusion in the penumbra by injection of

thrombolytic agents may prevent structural damage in this
area, thus limiting the neurological deficit. Ischemic stroke is an
emergency. The window of opportunity for salvaging the
penumbra is very short. If adequate blood supply is not
restored within 3 hours, necrosis extends to the penumbra.

PATHOLOGY OF ISCHEMIC INFARCTS

In the first day or so, the infarct appears as a poorly demarcated
area of softening.
 Old right MCA
infarct

Acute RACA infarct

Acute Right MCA infarct

Old right PCA

infarct

CT Imaging at this stage may be negative, especially in brain stem

infarcts. MRI is much more sensitive. At the peak of edema, the
infarct appears hypodense and bright on T2 MRI images. The
infarcted tissue becomes sharply demarcated and softens
progressively. From the second week onward, it begins
to disintegrate and is gradually replaced by a cavity. The size and
location of infarcts follows the anatomy of vascular territories.
 Neovascularization

Axonal swellings
Macrophages

Gemistocytic astrocytes

Microscopical examination

 in the first 24 to 48 hours reveals anoxic neurons, pallor of

staining and vacuolization of the white matter due to unraveling
of myelin, and axonal swellings.

 During the first week, there is a transient inflammatory

reaction, especially around blood vessels and in the meninges,
due to release of arachidonic and other fatty acids.

 As the core of the infarct disintegrates, endothelial cells from

the periphery proliferate, and capillaries grow into the dead
tissue.

 Neovascularization (which accounts for contrast

enhancement) peaks at 2 weeks.
  Monocytes from the blood stream enter the infarct through
damaged vessels. They ingest the products of degradation of
neurons and myelin and are transformed into lipid-laden
macrophages. Macrophage reaction appears early and peaks
at 3-4 weeks.

 Astrocytes from the surrounding undamaged brain proliferate

and form a glial scar around the infarct. This is completed in
approximately 2 months. After that, the infarct remains
unchanged.

 With maturation of new capillaries and glial scar formation, the

blood brain barrier is once again sealed. Neurons do not
regenerate. So, some brain tissue is lost forever.

Hemorrhagic infarct
HAEMORRHAGIC INFARCT

 A hemorrhagic infarct is an infarct stippled with petechiae or

showing confluent larger hemorrhages, especially in necrotic
gray matter.

 Blood leaks from collateral vessels or through necrotic

capillaries when the occluding thrombus or embolus breaks up
and the infarcted area is reperfused.

 Hemorrhagic infarcts are most common in embolism. Use of

thrombolytics or anticoagulants may convert a bland infarct into
a hemorrhagic one.

Lacunar infarcts
Lacunar infarcts

 Lacunar infarcts are small infarcts in the deeper parts of the

brain (basal ganglia, thalamus, white matter) and in the brain
stem.

 They are responsible for about 20 percent of all strokes. They

are caused by occlusion of deep penetrating branches of major
cerebral arteries and are particularly common
in hypertension and diabetes, which are associated with
severe atherosclerosis of small vessels and small vessel disease
(see below).

 A small lacunar infarct (e.g., one involving the internal capsule)

can cause as severe a neurological deficit as can a much larger
hemispheric infarct but without the life-threatening cerebral
edema that is seen in the latter.

CAUSES OF ISCHEMIC INFARCTION

The diverse types of vascular disease and other conditions that
cause cerebral infarction are partially listed in the table below and
briefly discussed further on.

Clinical classification systems for ischemic stroke, such as the

 TOAST (Trial of Org 10170 in Acute Stroke Treatment) and the

 ASCO (Atherosclerosis, Small vessel disease, Cardiac source,

Other cause) systems have been introduced.
  These systems are based on clinical and ancillary findings,
including noninvasive angiography and transthoracic
echocardiography.

 Atherothrombosis, small vessel disease, and cardioembolism

are the most common causes of ischemic stroke in elderly
patients.

 Cardioembolism and the other entities listed can cause stroke in

younger individuals, and some of them even in children.

Atherosclerosis-atherothrombosis

Small vessel disease

Cardioembolism, including paradoxical embolism through a patent foramen ovale

Vasculitis

Arterial dissection

Polycythemia, thrombocythemia, TTP

Systemic lupus erythematosus

Sickle cell disease

Vascular spasm

Meningitis and fungal vasculitis

Hypercoagulability (Factor V Leiden, Prothrombin 20210A mutation, antiphospholipid antibody syndrome)

Inherited metabolic disorders (Fabry disease, homocystinuria, mitochondrial disorders)

Fibromuscular dysplasia and other angiopathies

 Atherosclerosis and thrombosis

Severe atherosclerosis

A large proportion of infarcts are caused by atherosclerosis of

large arteries, alone or with superimposed thrombosis.

Atherosclerosis involves the circle of Willis and large leptomeningeal

arteries and extends into their smaller branches.
Atheromatous plaques begin with by intimal thickening and
accumulation of blood-derived lipids in the intima, followed by
disruption of the interna elastica, accumulation of lipid laden
macrophages, formation of cholesterol crystals, and deposition of
calcium. The process of lipid accumulation is accompanied by an
inflammatory reaction involving lymphocytes and macrophages.
Atheromatous plaques may cause narrowing or occlusion of the
vascular lumen by themselves or after rupture and thrombosis.
Cholesterol crystals from ruptured plaques may embolize distal
vessels.

Small vessel disease

Small vessel disease includes atherosclerosis of small arteries but

refers more specifically to lipohyalinosis and hyaline
atreriolosclerosis, vascular lesions that are seen primarily
in hypertension and diabetes but occur also in old age without
these predisposing conditions. This pathology affects small
penetrating arteries and arterioles that originate from the base of
the brain and supply the basal ganglia, thalamus, deep white
matter, and the brainstem.

Affected vessels become thickened, and the normal components of

their walls are replaced by a homogeneous, glassy (hyaline)
substance, composed of collagen and other proteins. Foamy
macrophages are present in lipohyalinosis.

The pathogenesis of this change varies: in hypertension, it is caused

by endothelial injury and leakage of plasma proteins in and around
vessels; in diabetes, it probably has to do with glycation of proteins
and diffuse basement membrane thickening. Its effects are
narrowing of the lumen and tortuosity, which lengthens the distance
blood has to travel to perfuse its targets.

Ischemia, resulting from these processes, causes small infarcts

(lacunar infarcts) and diffuse loss of axons and myelin in the white
matter (leukoaraiosis-thinning out of the white matter). Multiple
infarcts and leukoencephalopathy cause dementia.

In addition, loss of elasticity from destruction of smooth muscle

leads to development of small aneurysms and makes vessels fragile,
resulting in microbleeds and large catastrophic hemorrhages, which
occur spontaneously or after trivial trauma. See also genetic
angiopathies further on.
EMBOLIC

 According to some authors, embolism is the most frequent

cause of ischemic infarction.

 Most emboli are fragments of blood clots that originate in the

heart or major vessels. Conditions causing cardiac emboli
include myocardial infarcts, atrial fibrillation and other
arrhythmias, rheumatic heart disease, bacterial and non-
bacterial endocarditis, prosthetic valves, mitral valve prolapse,
atrial myxoma, calcified mitral annulus, and cardiomyopathy.

 An embolus cannot be distinguished grossly or microscopically

from a locally formed thrombus.

 An infarct is assumed to be embolic if it is hemorrhagic, there

is a source of emboli, there are multiple infarcts of the brain
and other organs (kidney, spleen), and there is no
atherosclerosis or other vascular disease. Some emboli consist
of atheromatous material that is detached from ulcerated
atheromas of the aorta or carotid arteries. Vascular
manipulation (angiography, carotid endarterectomy) may cause
atheromatous embolism. Rarer causes of embolism are fat, air,
and tumor emboli.

 \Unlike atherothrombotic infarcts, which may evolve within

hours or days, embolic infarcts have an abrupt onset.
Vasculitis
CNS vasculitis can be classified under the following categories:

Temporal (giant cell) arteritis

Mucor arteritis of the basilar
Aspergillus arteritis artery and pontine infarct

A. Systemic vasculitis with CNS involvement: giant cell

arteritis, polyarteritis nodosa, Wegener granulomatosis,
Takayasu arteritis, Kawasaki disease.

The most common of these entities is giant cell (temporal)

arteritis (GCA) which is more frequent in older people and
women and is associated with polymyalgia rheumatica.

GCA is also called temporal arteritis because it frequently

involves the temporal artery. Biopsy of the temporal artery is
done for diagnosis.
 However, GCA affects the aorta and other major extracranial
and, less frequently, intracranial branches.

Involvement of the ophthalmic artery causes visual loss in a

significant number of cases.

GCA is a T-cell mediated autoimmune condition that affects

medium-size and large arteries. Lymphocytes and
multinucleated giant cells infiltrate the vessel wall, disrupt the
internal elastic lamina, and cause narrowing and thrombosis.

B. Secondary vasculitis: Infectious (bacterial, fungal, spirochetal,

viral); collagen-vascular disease(SLE, rheumatoid arthritis, Behset
disease); drug-induced vasculitis. Fungal vasculitis is most
frequently caused by aspergillus and mucor.

C. Primary angiitis of the CNS (PACNS).

The criteria for PACNS are:

 The presence of neurologic or psychiatric deficits, a

 ngiographic or pathological documentation of vasculitis, and

 absence of evidence of systemic or secondary vasculitis.

Pathologically, PACNS can be subdivided into granulomatous

and nongranulomatous varieties.
 Granulomatous PACNS affects small and medium-size
leptomeningeal and cortical vessels and causes headaches,
seizures, focal deficits, and encephalopathy. Affected vessels
may have amyloid deposits, in addition to epithelioid cell
granulomas and giant cells. There is no vasculitis outside the
CNS.

 The nongranulomatous form shows lymphocytic

inflammation. PACNS that involves large vessels can be
detected by angiography and MRI imaging showing vascular
stenoses and ischemic strokes.

PACNS affecting small vessels presents with focal or diffuse

neurologic abnormalities and enhancing meningeal and
parenchymal lesions and is not evident on angiography. The
clinical picture overlaps encephalitis. The diagnosis of such
cases can be made by brain biopsy, which shows lymphocytic
inflammation in vessel walls and around vessels. This
inflammation may be difficult to distinguish from perivascular
mononuclear infiltrates that are seen in MS and infectious
diseases.
MCA infarct in sickle cell disease

Other causes of arterial occlusion and infarction include:

Hematologic disorders - Polycythemia, hemoglobinopathies

(sickle cell disease), deficiencies of anticoagulant factors, thrombotic
thrombocytopenic purpura.

Metabolic disorders - Dyslipoproteinemias, Fabry disease,

homocystinuria, organic acidemias, mitochondrial disorders. Some of
these conditions cause ischemic infarcts even in children and infants.
Mitochondrial disorders can cause TIAs and ischemic strokes.
Hereditary hypercoagulability disorders- Factor V Leiden,
Prothrombin 20210A. These polymorphisms derange the delicate
balance between natural anticoagulant and procoagulant pathways.
They are very prevalent in the population and combine with one
another and with aquired conditions that promote clotting, causing
venous and arterial infarcts.

Dissecting aneurysm

Trauma to the head and neck can cause dissecting

aneurysms and other lesions of the carotid and vertebral arteries.
The pattern of brain necrosis in severe traumatic brain injury often
suggests vascular occlusion. In some cases, arterial dissection
occurs apparently spontaneously, without a traumatic event.

Contraceptives and estrogen therapy cause most commonly

venous thrombosis and rarely intimal hyperplasia and thrombosis of
cerebral and extracerebral arteries.

Vascular Spasm. This is a complication of subarachnoid

hemorrhage.
Genetic angiopathies :

Cerebral autosomal dominant arteriopathy with subcortical infarcts

and ischemic leukoencephalopathy (CADASIL), caused by
mutations of the NOTCH3 gene, is a small vessel arteriopathy in
which deposition of a granular osmiophilic material in the vessel wall
causes loss of smooth muscle, thickening of the wall, and narrowing
of of the lumen. The symptoms are due to involvement of the brain
but the pathology affects other organs and tissues and can be
diagnosed with a skin biopsy.

An autosomal dominant angiopathy due to mutations of COL4A1,

which encodes a collagen of the vascular adventitia, causes
porencephaly in infants and a spectrum of disease in adults which
includes small vessel disease, lacunar infarcts, microhemorrhages,
deep intracerebral hemorrhages, intracranial aneurysms, and
leukoencephalopathy. Other COL4A1 related disorders are renal and
liver cysts, and eye abnormalities.

Cerebral amyloid angiopathy, caused by deposition of various

types of amyloid, causes similar vascular pathology but affects
primarily leptomeningeal and cortical vessels.

Miscellaneous: Spontaneous dissecting aneurysms,moya-moya

disease (narrowing of proximal cerebral arteries).

The fat embolism syndrome (FES) is a complication of long bone

fractures, orthopedic surgery, and traumatic lesions of the viscera
and subcutaneous tissue, including burns. The most common non-
traumatic cause of the FES in children and young individuals is sickle
cell disease. Other non-traumatic settings of FES include,
osteomyelitis, pancreatitis, and diabetes. Clinically, FES is
characterized by petechial rash, hypoxemia, deterioration of mental
status, and thrombocytopenia. Pathologically, there are petechial
hemorrhages and micro-infarcts in the brain, heart, and other
organs.

Fat embolism syndrome

Fat embolism syndrome

Fat, mobilized during trauma or osteonecrosis, enters the venous

circulation and embolizes pulmonary artery branches and capillaries.
If the capacity of pulmonary capillaries is exceeded or the lungs are
by-passed through a patent foramen ovale, fat globules enter the
arterial circulation and occlude capillaries in the heart, brain,
kidneys, and other organs, causing hemorrhagic and ischemic
lesions. There is some debate about the pathogenesis of the FES.
Some attribute it to mechanical obstruction by fat globules. Other
views maintain that it is caused by agglutination of chylomicrons
and toxic action of free fatty acids and other fat breakdown
products.

VENOUS INFARCT AND SINOVENOUS THROMBOSIS

Sinovenous thrombosis

Thrombosis of venous sinuses and their tributaries causes

congestion, hemorrhage, and necrosis of brain tissue (venous
infarction). Venous infarcts from thrombosis of the superior sagittal
sinus are parasagittal. The causes of venous thrombosis are diverse
and include oral contraceptives, inherited thrombophilias, cancer
and, in infants, dehydration. Sinovenous thrombosis accounts for
some cases of the syndrome of pseudotumor cerebri, which is
characterized by headache, papilledema, increased CSF pressure
and normal size ventricles. These symptoms and signs are caused
by intracranial hypertension which is due to impaired resorption of
CSF into the venous sinuses and venous congestion. This syndrome
has many other causes, including meningeal pathology, tumors,
toxic and metabolic disorders, and conditions that cause marked
elevation of CSF protein, such as the Guillain-Barré syndrome. In
many cases, no specific etiology is identified (idiopathic
intracranial hypertension)

VASCULAR DEMENTIA
About 10% of cases of dementia are caused by cerebrovascular
disease, most commonly multiple ischemic lesions. Examination, in
these cases reveals a combination of small or large infarcts,
hippocampal sclerosis, leukoencephalopathy due to cerebral amyloid
angiopathy or other small vessel disease, and other lesions. These
lesions affect cumulatively large areas of the cortex, especially
regions involved in memory and higher functions. Vascular
pathology may be combined with Alzheimer's disease or other
neurodegeneration.