Path Chapter 28: The Central Nervous System (1281-1313)
The functional unit of the CNS is the neuron
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Most mature neurons can’t do cell division, so destroying even a few neurons for a specific
function can cause a neuro deficit
Neuron injury:
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Acute neuron injury (“red neurons”) – happen at 12-24 hours after hypoxic/ischemic insult
o The neuron cell body shrinks, there’s pyknosis of the nucleus, the nucleolus disappears,
there’s loss of Nissl substance, and they have very eosinophilic cytoplasm
Subacte and chronic neuron injury (“degeneration”) – neuron death caused by a progressive
disease process that’s been going on for a bit
o The main characteristic is loss of cells
o Early in the process, the neurons may not be lost yet, but the glial cells may show
reactive changes that let you know there’s degeneration happening
o Often the cell loss is from apoptosis
o Neuron trans-synaptic degeneration – happens when there is a destructive process that
interrupts most of the afferent input to a group of neurons
Axonal reaction – rxn in the cell body that happens along with degeneration
o There’s increased protein making to allow for axon sprouting, which is seen as
enlargement and rounding up of the cell body, peripheral displacement of the nucleus,
enlargement of the nucleolus, and dispersion of Nissl substance form the center to the
periphery (called central chromatolysis)
Changes in the organelles and cytoskeleton
o Inclusions in neurons happen with aging from lipofuscin
o Viral infection would show viral inclusions
o Neurofibrillary tangles are seen in Alzheimer’s
o Lewy bodies of lipofuscin are seen in Parkinson disease
o Abnormal vacuoles are made in Creutzfeldt-Jakob disease
Astrocyte – called that cause it looks like a “star,” due to their multipolar branching cytoplasmic
processes that come from the cell body – page 1282
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Astrocyte cytoplasmic processes have glial fibrillary acidc protein (GFAP), which you can stain for
Astrocytes act as metabolic buffers and detoxifiers within the brain, and their foot processes
surround capillaries to work in barrier functions, controlling flow of things between the blood,
CSF, and brain (blood-brain barrier)
Gliosis – characterized by hypertrophy and hyperplasia
o Gliosis is the most important indicator of CNS injury
o In gliosis, the astrocyte nuclei enlarge, become vesicular, and develop a bright pink
cytoplasm around the nucleus, which has many ramifying processes coming from it
 These cells are called gemistocytic astrocytes
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When directly injured, astrocytes have their cytoplasm swell
 The insults cause the cells ATP dependent ion channels to fail, so they don’t
pump out sodium, and water moves in
Astrocytes can also get inclusions in their cytoplasm
 Rosenthal fibers – thick, elongated, brightly eosinophilc fibers in the astrocyte
processes, that have 2 heat shock proteins and ubiquitin
 Rosenthal fibers are found in places of long-standing gliosis, and are
characteristic of pilocytic astrocytomas (a glioma)
 Alexander disease -mutation to GFAP that causes lots of Rosenthal
fibers
 Corpora amylacea (aka polyglucosan bodies) – round, basophilic, PAS positive
structures made mostly of glycosaminoglycan polymers found wherever there
are astrocyte end processes
 They’re seen more as you age and may be a sign of astrocyte
degeneration
Oligodendrocytes and ependymal don’t respond to CNS injury
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Oligodendroglia wrap their cytoplasmic processes around axons to form myelin
o Each oligodendrocyte myelinates many internodes on multiple axons
o Injury or apoptosis of oligodendroglial cells is a characteristic feature of demyelinating
disorders and leukodystrophies
Ependymal cells – ciliated columnar epithelial cells lining the ventricles to make CSF
Microglia – mesoderm derived cells that are the resident macrophage of the CNS
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Microglia respond to injury by proliferating, developing elongated nuclei (rod cells), forming
aggregates at areas of necrosis (microglial nodules), and congregating around cell bodies of
dying neurons (neuronophagia)
Inflammation of the brain has macrophage from the blood as their main phagocyte
Things that can increase intracranial pressure include generalized brain edema, increased CSF volume
(hydrocephalus), and expanding masses
Cerebral edema:
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2 types of cerebral edema (edema of the parenchyma of the brain):
o Vasogenic edema – caused by blood-brain barrier disruption and increased vascular
permeability, causing fluid to shift from the blood to the intercellular spaces of the
brain
 The small amount of lymphatics in the brain impairs resorption of excess ECF
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Cytotoxic edema – increase in intracellular fluid (ICF) from neuronal, glial, or
endothelial cell membrane injury, like from a hypoxic/ischemic insult or with metabolic
damage
Often generalized edema has signs of both vasogenic and cytotoxic edema
Interstitial (hydrocephalic) edema – happens especially around the lateral ventricles when an
increase in intravascular pressure causes an abnormal flow of fluid from the intraventricular CSF
across the ependymal lining to the periventricular white matter
In generalized edema, the gyri are flattened, the intervening sulci are narrowed, and the
ventricular cavities are compressed
As the brain expands from the edema ,it can cause herniation
Hydrocephalus – accumulation of excessive CSF within the ventricular system – page 1283
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CSF is made by the choroid plexus in the ventricles, and enters the cistern magna at the base of
the brainstem through the foramens of Luschka and Magendie
Subarachnoid CSF bathes the superior cerebrum, & is absorbed by the arachnoid granulations
Most cases of hydrocephalus happen from impaired flow and resorption of CSF
o Overmaking of CSF is rarely the cause, from a tumor in the choroid plexus
The increased volume of CSF in the ventricles expands them, & can ↑ intracranial pressure
When hydrocephalus happens in infancy before the cranial sutures close, it enlarges the head,
seen as an increase in the head circumference
Hydrocephalus after the cranial sutures close, expands the ventricles and causes increased
intracranial pressure, without a change in head size
Noncommunicating hydrocephalus – when only a part of the ventricular system is enlarged form
the excess CSF
Communicating hydrocephalus – enlargement of the entire ventricular system
Hydrocephalus ex vacuo – dilation of the ventricular system with a compensatory increase in the
CSF volume secondary to loss of brain parenchyma
When the volume of the brain increases beyond the limit permitted by compression of veins and
displacement of CSF, the pressure within the skull will increase
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Most times this is from mass effect, which can be diffuse, like in generalized edema, or focal,
like with a tumor, abscess, or hemorrhage
Increased intracranial pressure can decrease perfusion of the brain, making cerebral edema
worse
Expansion of the brain can displace parts of it, and severe expansion can cause herniation
Types of herniations – page 1283 bottom pic
o Subfalcine (cingulate) herniation – when unilateral or asymmetric expansion of a
cerebral hemisphere displaces the cingulate gyrus under the falx cerebri
 This can compress branches of the anterior cerebral artery
o Transtentorial (uncinate, mesial temporal) herniation – when the medial part of the
temporal lobe is compressed against the free margin of the tentorium
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This can compress CN 3, causing pupil dilation and problems with eye
movements, on the side of the lesion
 Transtentorial herniation can also compress the posterior cerebral artery,
causing ischemia to the visual cortex
 A large transtentorial herniation can compress the contralateral cerebral
peduncle, called Kernohan’s notch, causing hemiparesis on the side of the
herniation
 Progression of transtentorial herniation often includes hemorrhagic lesions in
the midbrain and pons, called secondary brainstem (Duret) hemorrhages
 They’re linear or flame shaped lesions in the midline from hurting veins
and arteries supplying the upper brainstem – page 1284
Tonsilar herniation-displacement of the cerebellar tonsil through the foramen magnum
 Tonsillar herniation is life threatening, because it causes brainstem
compression and compromises vital respiratory and heart centers in the
medulla oblongata
Neural tube defects – failure of part of the neural tube to close, or reopening it after it has closed
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Neural tube defects show problems of the neural tissue, meninges, and overlying bone or soft
tissue
Neural tube defects are most CNS malformations
Encephalocele- malformed CNS tissue sticks out the cranium
o Encephaloceles usually happen in the occipital area or posterior fossa
The most common neural tube defects involve the spinal cord reopening or failure of the caudal
part of the spinal cord to close, called spina bifida
o Spina bifida oculta – asymptomatic bony defect
o Other spina bifidas are severe malformations with a flattened disorganized segment of
spinal cord, with an overlying meningeal outpunching
o Myelomeningocele – both the spinal cord and meninges are sticking out
 Meningocele – extrusion when only the meninges are sticking out
 Myelomeningoceles are most common in the lumbosacral region
 People with myelomeningoceles have motor and sensory problems in the
lower extremities, and disturbances of bowel and bladder control from both
cord problems and superimposed infections
Folate deficiency during the beginning of pregnancy is a risk factor for a neural tube defect
You screen for a neural tube defect with imaging and taking samples of mom’s blood to look for
increased α-fetoprotein
Anencephaly – the anterior end of the neural tube doesn’t form right, so there’s no brain
o Forebrain development is messed up at about day 28 of development, so you get a
flattened remnant of brain tissue with mixed CNS stuff, called an area cerebrovasculosa
Forebrain anamolies:
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Megaloencephaly – large volume of the brain (big brain)
Microencephaly – small volume of the brain, way more common
o Microencephaly can happen from chromosome problems, fetal alcohol syndrome, and
HIV in utero
o It’s thought microencephaly happens from decreased #’s of neurons reaching the
neocortex, leading to a simplification of the gyral folding
o The precursors of the developing brain are found next to the ventricles, and the # of
eventual neurons is determined by how many of them transition into migrating cells
o At first, cell division of the progenitor gives you two new progenitors, but eventually you
starting dividing into one progenitor and one going to the developing cortex
o If too many cells exit the proliferating pool too early, then you generate less neurons
o If too few exit during the early rounds of division, you get an overmaking of neurons
Lissencephaly (agyria) – no gyri, so brain is smooth, caused by mutations to LIS-1 or αdystroglycan – page 1285
Polymicrogyria –small, abnormally numerous, & irregularly formed gyri
o The gray matter will have 4 or less layers, and the meningeal tissue will be entrapped at
points of fusion
o Polymicrogyria can be induced by tissue injury toward the end of neuronal migration
Neuronal herotopias – migrational disorders caused by collections of neurons in the wrong
spots along migrational pathways
o Neuronal heterotopias often cause epilepsy
o One of these wrong spots is the ventricles if they never left their site of origin
 Periventricular heterotopias are caused by mutation to the gene for filamin A
Holoprosencephaly – incomplete separation of the cerebral hemispheres across the midline
o Holoprosencephaly shows midline facial problems, like cyclopia, and loss of CN 1
(olfactory)
o Trisomy 13 and sonic hedgehog can cause holoprosencephaly
 Sonic hedgehog is a protein made by the notochord and neural plate during
neural development
Agenesis of the corpus callosum – common malformation of absence of the white matter
bundles that carry cortex projections from one hemisphere to the other
o Radiograph will show misshapen ventricles (“batwing deformity”) – page 1285
o Agenesis of the corpus callosum can be asymptomatic or cause mental retardation
Posterior fossa anomalies:
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Dandy-Walker malformation – enlarged posterior fossa, which lacks the cerebellar vermis, and
replaces it with a midline cyst that is an expanded 4th ventricle
Arnold-Chiari malformation (Chiari 2 malformation) – small posterior fossa, misshapen middle
cerebellum with the vermis going downward through the foramen magnum, hydrocephalus,
and a lumbar myelomeningocele
Chiari 1 malformation – cerebellar tonsils extend down into the vertebral canal
Hydromyelia – expansion of the central canal of the spinal cord
Syringomyelia (aka syrinx) – a fluid filled cavity forms in the inner spinal cord
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When it goes into the brainstem it’s called a syringobulbia
Syringomyelia can happen in the Chiari 1 malformation, tumors, or after trauma
A syrinx causes destruction of the nearby gray and white matter, causing loss of pain and
temperature in the upper extremities because it prefers to happen at the crossing of the
anterior spinal commissural fibers of the spinal cord
Cerebral palsy – neuro motor defecit that doesn’t progress, and shows spasticity, dystonia, ataxia, and
paresis, all due to insults before or during birth
Premature babies are at increased risk for intraparenchymal hemorrhage and infarcts of the
supratentorial periventricular white matter (periventricular leukomalacia)
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Periventricular leukomalacia shows yellow plaques with white matter necrosis and calcification
o When it also involves the gray matter, it’s called multicystic encephalopathy – p. 1286
Perinatal ischemia often affects the sulci the most, causing thinned gliotic gyri called ulegyria
The effects of CNS trauma is determined mainly by where the lesion is and the limited ability of the
brain to repair it
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Ex: tiny injury could be silent in the frontal lobe, very disabling in the spinal cord, and fatal in the
brainstem
A blow to the head can cause skull fractures, parenchymal injury, and vascular injury
Displaced skull fracture – break where bone is displaced into the cranial cavity by a distance
greater than the thickness of the bone
o If there’s symptoms of the lower CN’s and orbital or mastoid hematomas, it’s probably a
basal skull fracture, which usually follows a blow to the occiput or side of the head
Diastatic fractures – the break crosses a suture
Brain parenchymal injuries:
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Concussion – syndrome of altered consciousness secondary to head injury, usually a change in
the momentum of the head (so a moving head is suddenly stopped by impact with something)
o Characteristic symptoms of a concussion include instant transient neuro changes, like
loss of consciousness, they temporarily stop breathing, and loss of reflexes
o Neuro recovery from a concussion can be complete, but often they still have amnesia
Brain contusion – bruise of the brain
Brain laceration – cut on the brain tissue
Any blow to the head leads to displacement of brain tissue, which can disrupt vascular channels
and lead to hemorrhage, injury, and edema
o The gyri are most susceptible to contusion or laceration cause they face the most force
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A person who takes a blow to the head can develop a contusion at the point of contact (coup
injury) or a contusion on the contralateral brain surface (contrecoup injury)
o If the head is immobile at the time of the blow, you just get coup injury
o If the head was mobile, you get bout coup and contrecoup
o Coup is from the contact between the brain and skull at the site of the blow to the head,
and contrecoup is caused by when the brain strikes the opposite side of the skull after
sudden deceleration
Sudden impacts that cause violent hyperextension of the neck can separate the pons from the
medulla or the medulla from the cervical cord, causing instantaneous death (like when a car hits
someone from behind)
Contusions look wedge shaped on the surface of the brain
o In the early stages there’s edema and hemorrhage around the capillaries
o In the next few hours, the leaked out blood extends throughout the involved tissue,
across the width of the cerebral cortex, and into the white matter & subarachnoid space
o Neuron injury is seen as pyknosis of the nucleus, eosinophila of the cytoplasm, and
disintegration of the cell, and takes about 24 hours to appear
o Then there’s normal CNS inflammation with neutrophils followed by macrophage
o Old traumatic contusion lesions are characteristically depressed, retracted, yellowbrown patches involving the crests of gyri most often at the sites of contrecoup lesions,
with a lot of gliosis and hemosiderin-filled macrophage
o The contusion can become a site of an epileptic foci
When white matter is hurt by the trauma, it causes diffuse axonal swelling called axonal injury
o Half of people who develop a coma from the trauma have diffuse axonal injury
Vascular injury is common with CNS trauma, due to disruption of the vessel wall from it, leading to
hemorrhage
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Hemorrhage can happen into the epidural, subdural, subarachnoid, and intraparenchymal
compartments – page 1289
Subarachnoid and intraparenchymal hemorrhages most often happen along with brain trauma
that caused contusions and lacerations
Epidural hematomas – when a torn vessel causes the dura to separate from the skull surface
o Normally the dura is fused with the periosteum on the internal surface of the skull
o Dural arteries, especially the middle meningeal artery, are vulnerable to injury,
especially with temporal skull fractures where the fracture line crosses the vessel
o Once a vessel has been torn, the leak of blood from arterial pressure can cause the dura
to separate from the inner surface of the skull – page 1289 bottom pic
o If the blood accumulates slowly, the person may be fine for several hours before neuro
symptoms show up
o Epidural hematomas can expand rapidly, and is a neuro emergency that needs drained
o Epidural hematomas are usually caused by a rupture of a cranial artery, not a vein
Subdural hematomas – rupture of veins in the subdural space
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Subdural space – space between the inner surface of the dura mater and the outer
arachnoid layer of the meninges
Bridging veins from the cerebral hemispheres travel in the subarachnoid and subdural
spaces to empty into the superior sagittal sinus
These veins are prone ot tear in the subdural space, causing bleeding that leads to a
subdural hematoma
The brain can move because it floats on CSF, but the venous sinuses can’t move, so
moving the brain in trauma can tear the veins where they enter the dura
In old people with brain atrophy, the bridging veins are stretched out and the brain has
increased space to move in, so subdural hematomas are more common in old people,
and happen easier from more minor trauma
Infants are also prone to subdural hematomas cause their bridging veins have thin walls
An acute subdural hematoma looks like a collection of freshly clotted blood on the brain
surface, that does not extend into the sulci – p. 1290
 Usually, the bleeding from the vein is self-limited, and the hematoma is broken
down and organized over time
 After about a week, the clot is lysed, then at the 2nd week, fibroblasts
grow from the dural surface into the hematoma, forming fibrous tissue
over several months
 The organized hematoma is attached by fibrous tissue only to the dura and not
to the arachnoid
 Eventually the lesion can retract until there’s just a thin layer of connective
tissue, called a “subdural membrane”
Subdural hematomas commonly have episodes of repeat bleeding, because the
granulation tissue vessels have thin walls
Subdural hematomas most often show up within 48 hours of the injury, and are most
common over the lateral part of the cerebral hemispheres, usually showing headache
and confusion
Post-traumatic hydrocephalus – block of CSF resorption from hemorrhage into the subarachnoid spaces
Post-traumatic dementia and punch-drunk syndrome (another dementia) can happen after repeated
head trauma in a short time period
Findings after a head trauma can include hydrocephalus, thinned corpus collosum, diffuse axonal injury,
neurofibrillary tangles, and amyloid plaques
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Brain trauma can also cause post-traumatic epilepsy, tumors, infections, & psychiatric problems
Spinal cord trauma:
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Lesions of the cervical cord can cause quadriplegia
o Those above C4 can also paralyze the diaphragm, causing respiratory compromise
Lesions of the thoracic cord or below can cause paraplegia
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Damage to the descending and ascending white matter of the spinal cord cause you to lose the
connection between the brain and the spinal cord, which is the main cause of neuro problems
from spinal cord injury
At the level of injury, there will be hemorrhage, necrosis, and axonal swelling in the surrounding
white matter
o In time, the lesion becomes cystic and gliotic, with the cord above and below the injury
showing wallerian degeneration of the white matter tracts
Cerebrovascular disease (CVA) is the 3rd leading cause of death in the US
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Involves thrombosis, embolism, and hemorrhage
“stroke” is the term applied to all of them in the head
Think of cerebrovascular disease in two ways:
o Hypoxia, ischemia, and infarction from lack of oxygen to the CNS
o Or the vessel ruptures and hemorrhages
The brain needs a constant supply of glucose and oxygen
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Although the brain is only 2% the body weight, it receives 15% of resting cardiac output, and
consumes 20% of the body’s oxygen
Cerebral blood flow stays pretty constant over a wide range of blood and cranial pressures, through
autoregulation
The brain is highly aerobic, meaning oxygen, instead of available substrate, is rate limiting
Ways to deprive the brain of oxygen:
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Hypoxia – low Po2, decreased blood oxygen-carrying capacity
Ischemia
When blood flow to a part of the brain is decreased, survival of the tissue depends on if there’s
collateral vessels, how long the ischemia is, and how fast and bad the decreased flow is
The metabolic decrease in energy caused by ischemia can cause inappropriate release of
neurotransmitters, like glutamate
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Glutamate triggers cell damage by allowing excess influx of calcium through NMDA glutamate
receptors, leading to cell death mostly through necrosis
o The increased intracellular calcium can then trigger all kinds of problems, including
inappropriate activation of signal cascades, free radicals, and mitochondria damage
The area between the normal and necrotic brain tissue, is called “at-risk” tissue or “penumbra”
Hypotension can cause global cerebral ischemia
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In mild hypotension, there may only be some confusion after the ischemia, followed by
complete recovery, and no irreversible damage; or there may be irreversible damage
Neurons are the most sensitive nervous cells to ischemia
In severe global cerebral ischemia, widespread neuron death happens
o Patients who survive it, often remain in a persistent vegetative state
o Others can undergo “brain death” caused by irreversible injury to the cortex or
brainstem, or a loss of brain perfusion
 When these people are maintained on mechanical ventilation, the brain
gradually breaks itself down, called “respirator brain”
Border zone (watershed) infarcts- happen in areas of the brain or spinal cord that are very
distant from the arterial blood supply
o They’re in the border zones between two separate artery supply areas
o In the cerebral hemispheres, the border zone between the anterior and middle cerebral
artery areas is most at risk
 Damage to this area causes a sickle-shaped band of necrosis over the cerebral
convexity
o Border zone (watershed) infarcts are usually seen after hypotensive episodes
In global ischemia:
o The brain is swollen, the gyri are widened, and the sulci are narrowed
o When you get to irreversible ischemic injury (infarction), 3 phases happen:
 Early changes – 12 to 24 hours after the insult – page 1292
 Shows acute neuron changes, called red neurons
o Characterized by microvacuolization, then eosinophilic neuron
cytoplasm, and later nucleus pyknosis and karyorrhexis
 Similar changes happen a bit later in the glial cells
 Pyramidal cells of the hippocampus, Purkinje cells of the cerebellum,
and cortex pyramidal neurons, are the most susceptible to the ischemia
 Neutrophils then move in
 Subacute changes- 24 hours to 2 weeks
 Includes necrosis of the tissue, influx of macrophage, vascular
proliferation, and reactive gliosis
 Repair- after 2 weeks
 Necrotic tissue is removed, the organization of the CNS structure is lost,
and gliosis
Cerebral artery occlusions can cause localized ischemia, which can lead to infarction of those areas the
vessel supplies
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The major source of collateral flow is the circle of Willis
o Cortical-leptomeningeal anastomoses also help the anterior, middle, and posterior
cerebral arteries
o There is little to no collateral flow for deep penetrating vessels
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Most thrombotic occlusions are from atherosclerosis
o The most common sites of a thrombus are:
 The carotid bifurcation
 Origin of the middle cerebral artery
 Either end of the basilar artery
Embolism to the brain can happen most often from heart mural thrombi
o The middle cerebral artery is most commonly affected
o Emboli tend to lodge where arteries branch, or where there’s already a stenosis
Inflammation can also cause narrowing of vessels that causes infarcts
o Infectious vasculitis could do it and is common in immunosuppressed people
o Polyarteritis nodas is a noninfectious cause
o Primary angiitis of the CNS – inflammatory disorder in small and medium sized vessels of
the CNS, causing chronic inflammation, giant cells, and destruction of the vessel wall
Hypercoagulation, dissecting aneurysms, and drugs can also cause infarcts
Two types of infarcts:
o Hemorrhagic infarcts (aka red infarcts) – usually associated with embolism
 The hemorrhage is thought to be secondary to reperfusion of damaged vessels
and tissue
o Nonhemorrhagic infarcts (aka pale infarcts) – usually associated with thrombosis
o Important to know what kind it is, since thrombolytics help nonhemorrhagic, but make
hemorrhagic worse (you’re bleeding)
 Thrombolytics will only work for a short time period after onset of symptoms
Morphology of infarcts:
o Nonhemorrhagic infarcts
 Not much is seen until 48 hours, when the tissue is now pale, soft, and swollen
 At 2-10 days, the brain becomes friable, and edema resolves, and you can tell
the difference better between normal and abnormal cells
 From 10 days-3 weeks, the tissue liquefies, eventually leaving a fluid-filled
cavity lined by dark-gray tissue, that will expand as dead tissue is removed
 At the microscopic level:
 At 12 hours, red neuron from ischemia is seen, and edema is present
 Glial cells swell, and the myelinated fibers disintegrate
 Neutrophils invade for up to 48 hours, then decreases, as macrophage
show up and become the most numerous cell for 2-3 weeks
 As liquefaction and phagocytosis happens, the astrocytes nearby get
bigger and help out
 After several months, the astrocyte response recedes, leaving behind a
dense meshwork of glial fibers mixed with new capillaries and CT
 In the cerebral cortex, a glial layer of tissue separate the liquid cavity
from the meninges and subarachnoid space
 Infarcts heal this way from the edges inward, so may see different stages
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Hemorrhagic infarcts- same thing, with blood extravasation and resorption
The most important effects of hypertension on the brain are lacunar infarcts, slit hemorrhages,
hypertensive encephalopathy, and massive hypertensive intracerebral hemorrhage
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Lacunar infarcts
o Hypertension can cause sclerosis and occlusions in deep penetrating arteries and
arterioles
o Cerebral vessel lesions in the CNS can cause many, small, cavitary infarcts called lacunae
 They’re “lake-like” spaces (lacunae)
 On microscope they’ll show tissue loss with scattered lipid filled macrophage
and gliosis
o Lacunae can be asymptomatic or cause neuro problems
Slit hemorrhages-small leaks from rupture of small penetrating vessels in hypertension
o The hemorrhage will resorb, leaving behind a “slit-like” cavity surrounded by brownish
tissue
o They also show tissue destruction, scattered lipid filled macrophage and gliosis
Hypertensive encephalopathy – problems that show up from acute hypertension
o Includes headaches, confusion, vomiting, convulsions, and can lead to coma
o Need to decrease the intracranial pressure
People who over a chronic time period get many gray and white matter infarcts may develop
vascular dementia
o Shows dementia and gait problems
o Caused by hypertension, atherosclerosis, and thrombosis in the brain vessels
o Called Binswanger disease when the injured area is more white matter
Primary hemorrhages in the epidural or subdural space are usually from trauma
Hemorrhages in the brain parenchyma or subarachnoid space are more often caused by
cerebrovascular disease (like a stroke)
Spontaneous (nontraumatic) intraparenchymal hemorrhages usually happen later in life
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Most are caused by rupture of a small intraparenchymal vessel
Can be distinguished into lobar hemorrhages (cortex lobes) and ganglionic hemorrhages (basal
ganglia or thalamus)
The major causes of intraparenchymal hemorrhage are hypertension and cerebral amyloid
angiopathy
o Hypertension causes about half the intraparenchymal hemorrhages
o Hypertension speeds up atherosclerosis in big arteries, hyaline atherosclerosis in little
arteries, and can cause necrosis when severe in the arterioles
 Hyaline change makes walls weaker
o Sometimes chronic hypertension can cause tiny aneurysms, called Charcot-Bouchard
microaneurysms
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 Happens mostly in small vessels, and usually at the basal ganglia
o Half the time, hypertensive intraparenchymal hemorrhage originates in the putamen
o Acute hemorrhages release blood that compresses the brain parenchyma
o Old hemorrhages will show an area of cavitary destruction of brain, with brown
discoloration around it
Cerebral amyloid angiopathy (CAA) – amyloid peptides deposit in the walls of head vessels
o This can weaken the vessel wall and risk hemorrhage
o Involved vessels look stiff
Over weeks to months, the hematoma can gradually resolve and improve symptoms
Subarachnoid hemorrhage
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The most common cause of subarachnoid hemorrhage is rupture of a saccular (berry) aneurysm
o Saccular(berry) aneurysm is the most common type of intracranial aneurysm
Saccular aneurysms are usually in the anterior circulation – page 1297
Cigarette smoking and hypertension increase your risk for berry aneurysms and hemorrhage
An unruptured saccular aneurysm is a thin-walled outpouching, usually at an arterial branch
point along the circle of Willis, or a major vessel just beyond it
Rupture usually releases blood into the subarachnoid space, brain, or both
Rupture can happen at any time, but 1/3 of the time, it happens when intracranial pressure
increases, like in straining to poop
Blood under arterial pressure is forced into the subarachnoid space, and the patient gets a
sudden excruciating headache described as “the worst I’ve ever felt”
They then quickly lose consciousness
¼-1/2 die on the first rupture, but those who survive often improve and recover consciousness
in minutes
Repeat bleeding is common in survivors, and every time they bleed, the prognosis gets worse
In the first few days after a subarachnoid hemorrhage, there’s increased risk of more ischemic
injury from vasospasm affecting vessels bathed in the released blood
Vascular malformations:
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Arteriovenous and cavernous malformations cause risk of hemorrhage
o Arteriovenous malformations involve vessels in the subarachnoid space that go into the
brain parenchyma, or can happen exclusively in the brain
 It’s a tangle of vessels with shunting and high flow
 Most commonly happens in the middle cerebral artery
o Cavernous malformations are vessel dilations that have low flow and no shunting
Infection can hurt the nervous tissue by direct injury to neurons or glia, or through toxins,
inflammation, or the immune system
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4 ways for infection to get into the nervous system:
o Through blood – most common, usually through arteries
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Directly putting it there through trauma
Local extension from nearby areas – sinuses, infected tooth, osteomyelitis
PNS – viruses like HSV, etc.
Meningitis – inflammation of the meninges and CSF within the subarachnoid space
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Acute meningitis can be pyogenic (bacteria), aseptic (usually viral), and chronic
Encephalitis – inflammation of the brain parenchyma
Acute pyogenic (bacterial) meningitis:
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In neonates, bacterial meningitis is usually E. coli or group B strep
In old people, bacterial meningitis is usually strep pneumonia or listeria monocytogenes
In teens and young adults, bacterial meningitis is usually Neisseria meningitides
Infants used to get bacterial meningitis from H flu a lot, but now we have a vaccine, so the main
cause is usually strep pneumonia
Symptoms of acute bacterial meningitis include headache, photophobia, irritability, clouding of
their consciousness, and neck stiffness
Spinal tap of bacterial meningitis shows cloudy or purulent CSF, with increased pressure, lots of
neutrophils, increased protein, and decreased glucose
Waterhouse-Friderichsen syndrome – hemorrhagic infarction of the adrenals due to septic
spread from a meningitis, and shows skin petechiae
o The most common cause is meningococcal or pneumococcal meningitis
Acute meningitis has an exudate in the meninges and surface of the brain
The meningeal vessels are engorged
The inflammation can move into the cerebrum (focal cerebritis), and block blood supply to the
brain to cause hemorrhagic infarction
Fibrosis from the inflammation can follow and cause hydrocephalus, or affect the arachonoid to
cause chronic adhesive arachnoiditis
Bacterial meningitis can be life-threatening without treatment with antibiotics
Acute aseptic (viral) meningitis – means there’s no organism seen in someone with meningitis
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Aseptic meningitis is usually caused by a virus, & is usually less severe than bacterial meningitis
Aseptic meningitis shows high lymphocytes (lymphocyte pleocytosis), only moderate increase in
proteins, and normal glucose
Viral aseptic meningitis is usually self-limiting
Brain abscess – focal brain infection
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Brain abscesses can happen from direct implantation of organisms, local extension from nearby
areas (mastoiditis, sinusitis), or spread through blood (usually from heart, lungs, bone, or tooth
extraction)
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Things that predispose to a brain abscess include acute bacterial endocarditis, congenital heart
disease with right-to-left shunts (so lungs don’t get rid of bugs), chronic pulmonary sepsis, and
immunosuppression
The most common bugs that cause a brain abscess are staph or strep when they’re not
immunocompromised
Brain abscesses show central liquefactive necrosis surrounded by fibrosis and swelling
Symptoms of the brain abscess will always show signs of increased intracranial pressure, along
with whatever signs would be caused by problems at that specific area
The CSF in a brain abscess shows increased pressure, high WBCs, high protein, & normal glucose
Increased intracranial pressure leading to herniation from the abscess can be fatal
If the abscess ruptures, it can lead to infection of the ventricles, meninges, and venous sinus
thrombosis
Brain abscesses are life-threatening without treatment, but antibiotics and surgery work well
Subdural empyema – when infection of the skull bones or sinuses spread to the subdural space
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A subdural empyema can cause mass effect, and also cause thrombophlebitis in the bridging
veins that cross the subdural space, causing venous occlusion and infarction of the brain
Most patients have fever, headache, neck stiffness, & if untreated neuro signs, lethargy, &
coma
The CSF will look the same as it would in a brain abscess
Chronic bacterial infection of the meninges and brain can be caused by M. tuberculosis, T. pallidum,
and some Borrelia
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Tuberculosis of the brain can spread there from silent pulmonary lesion, and can involve the
brain, meninges, and most often it involves both (meningoencephalitis)
o In tuberculosis, the subarachnoid space will have a gelatinous or fibrinous exudate,
usually at the base of the brain, that obliterates the cisterns are wraps around CN’s
o There may be white granules scattered over the meninges
o There will be granulomas with caseous necrosis and giant cells in tuberculosis
o The arteries in the subarachnoid space may show obliterative endarteritis from
inflammation of the vessel wall, with intimal thickening
o Sometimes, there can be an intraparenchymal mass called a tuberculoma, which causes
mass effect, that has a central core of caseous necrosis surrounded by granulomas
o Symptoms of tuberculosis meningitis include headache, malaise, confusion, and
vomiting
o CSF in tuberculosis shows moderate increase in WBCs, usually very high protein, and
normal or decreased glucose
o The most serious complications of chronic tuberculous meningitis is arachnoid fibrosis
causing hydrocephalus, and obliterative endarteritis causing occlusion and infarct of
the underlying brain
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Neurosyphilis – the tertiary stage of syphilis that happens in about 10% of those who haven’t
been treated for trepenoma pallidum infection yet
o The major patterns of neurosyphilis are meningovascular neurosyphilis, paretic
neurosyphils, and tabes dorsalis
o Meningovascular neurosyphils – when T. pallidum invades the meninges, causing a
chronic meningitis involving the base of the brain and spinal meninges
 Often there is obliterative endarteritis with perivascular inflammation full of
lymphocytes
 Cerebral gummas – plasma cell-rich mass lesions in the meninges and brain
o Paretic neurosyphils – when T. pallidum invades the brain, & shows progressive mental
deficits with mood changes, that become severe dementia (paresis of the insane)
 Often paretic neurosyphilis involves the frontal cortex, and shows inflammation
characterized by loss of neurons, proliferations of microglia, gliosis, and iron
deposits
 You’ll see the treponoma spirochetes
 There can be hydrocephalus that hurts the ependymal lining and causes
proliferation of ependymal glia, called granular ependymitis
o Tabes dorsalis – when spirochetes hurt the sensory nerves in the dorsal roots of the
spinal cord, causing problems with joint position sense leading to ataxia, loss of pain
sensation, lack of deep tendon reflexes, and characteristic “lightning pains”
 There will be loss of axons and myelin in the dorsal roots, causing pallor and
atrophy in the dorsal columns of the spinal cord
Neuroborreliosis – lyme disease causes CNS problems
o Lyme disease is caused by the spirochete borrelia burgdorferi, transmitted by ticks
Viral encephalitis almost always includes meningeal inflammation (meningoencephalitis), and
sometimes involves the spinal cord (encephalomyelitis)
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Many viruses that infect the CNS do so as latent infections
Intrauterine viral infection can cause congenital malformations, like in rubella
Arbovirus can cause encephalitis, especially in tropical areas of the world
o Arbovirus can cause serious encephalitis with high mortality
o All arbovirus have an animal host and mosquito vector, and includes West Nile
o Symptoms of arbovirus in the CNS include generalized stuff like seizures, confusion,
delirium, and stupor or coma, and focal signs like reflex asymmetry and ocular palsy
o West Nile in the spinal cord can cause paralysis
o CSF in arbovirus has slightly elevated pressure, lymphocytes, high protein, and normal
glucose
Herpes simplex virus type 1 (HSV-1) encephalitis is most common in kids and young adults
o Only about 10% of people with HSV-1 encephalitis have a history of prior herpes
o The most common presenting symptoms from HSV-1 encephalitis are changes in mood,
memory, and behavior
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Antivirals treat the HSV-1, lowering mortality rate
HSV-1 encephalitis starts in, and most severely involves, the medial temporal lobes
(memory) and the orbital gyri of the frontal lobes
o The infection is necrotizing and often hemorrhagic, with perivascular cuffs of
lymphocytes, and viral inculsions
HSV-2 can cause meningitis in adults, but is more common in newborns because half of
newborns born of vaginal delivery to women with active primary HSV genital infections will
acquire it and develop severe encephalitis
Primary varicella zoster virus (herpes zoster) infection presents as chickenpox, without any
neuro issues
o After the skin infection, varicella enters a latent phase in the sensory neurons of the
dorsal root or trigeminal ganglia
o When it reactivates in adults (shingles) it causes painful blisters on the skin along the
dermatome of the sensory neuron
o Varicella is usually self-limited, but can cause a persistent postherpetic neuralgia,
especially when they’re older, with persistent pain and painful sensation after
nonpainful stimuli
o Varicella rarely involves the CNS, but when it does it can be severe
o Varicella can cause a granulomatous arteritis
o Varicella encephalitis is characterized by demyelination followed by necrosis
Cytomegalovirus (CMV) infects the nervous system of the fetus and immunosuppressed people
o CMV causes periventricular necrosis that causes severe brain destruction, followed by
microcephaly and periventricular calcification
o CMV is a common opportunistic viral pathogen in people with AIDS
o In immunosuppressed people, CMV usually causes encephalitis that shows CMV
inclusions
o CMV can infect any neural cell, but likes the ventricles and subependymal areas,
involving the choroid plexis
Paralytic poliomyelitis has been mostly eradicated by vaccine, but it’s still out there in some
parts of the world
o Polio causes gastroenteritis, which can rarely involve the nervous system
o Polio likes the anterior horn motor neurons of the spinal cord, showing loss of neurons
and gliosis, inflammation, and atrophy of the motor spinal roots, leading to atrophy of
the denervated muscle
o CNS symptoms of polio start w/ meningeal irritation & CSF similar to aseptic meningitis
 It can stop there, or then progress to the spinal cord
o When polio affects the motor neurons of the spinal cord, it causes a flaccid paralysis
with muscle wasting and hyporeflexia, which are permanent
 Paralysis of the respiratory muscle can cause death
o Decades after the polio onset they can develop post-polio syndrome of progressive
weakness with pain and decreased muscle mass
Rabies – severe encephalitis transmitted to humans by bites from a rabid animal (usually dog)
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Rabies causes intense brain edema with widespread neuron degeneration, and an
inflammation that is most severe in the brainstem
o The characteristic finding of rabies are Negri bodies, which are rabies viral inclusions in
the pyramidal neurons fo the hippocampus & purkinje cells fo the cerebellum – p. 1304
o Rabies enters the CNS by ascending along the peripheral nerves from the wound site
 So there’s an incubating period of 1-3 months depending on how long it takes
to get up there from the wound to the brain
o Rabies starts with nonspecific symptoms of malaise, headache, and fever, but also has
at the same time diagnostic paresthesia around the wound
o As the rabies advances, the person has extraordinary CNS excitability where the
slightest touch is painful, with violent motor responses progressing to convulsions
o Rabies causes the pharyngeal muscles to contract on swallowing, causing foaming at
the moth
o There is menigismus (meningeal irritation), flaccid parylysis, periods of alternating
mania and stupor, which then progress to coma and death from respiratory failure
HIV aseptic meningitis happens within 1-2 weeks of seroconverision in about 10% of patients
o You’ll see antibodies to HIV in the CSF
o HIV can cause a mild lymphocytic meningitis, perivascular inflammation, and some
myelin loss in the cerebral hemispheres
o In the CNS, only microglia have the CD4 and chemokine receptor (CCR5 or CXCR4) to
allow for HIV infection
o HIV encephalitis is characterized by chronic inflammation with microglial nodules, and
multinucleated giant cells
o The effect of HIV in the CNS is HIV-associated dementia, and how bad it is depends on
how many microglia are infected
Progressive multifocal luekoencephalopathy (PML) – viral encephalitis caused by the JC
polyomavirus, which prefers to infect oligodendrocytes and cause mainly demyelination
o PML happens almost entirely in immunosuppressed people, which lets the JC virus
reactivate
o PML destroys patches of white matter, showing demyelination, most often subcortical
o The oligodendrocyte will have an enlarged nuclei with glassy viral inclusions
Subacute sclerosing panencephalitis (SSPE) – rare progressive cognitive decline, spasticity of
limbs, and seizures , in kids or young adults months to years after a measles infection
o The viral inclusions have nucleocapsids characteristic of measles
o SSPE has basically disappeared thanks ot measles vaccine
Fungal infection of the CNS happens mainly in immunocompromised people, usually by candida
albicans, mucor species, aspergillus fumigatus, and Cryptococcus neoformans
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3 main patterns of fungal infection in the CNS: chronic meningitis, vasculitis, and parenchymal
invasion
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Vasulitis most often happens with mucormycosis and aspergillosis, where the fungus
directly invades the vessel wall
 This causes vascular thrombosis that causes hemorrhagic infarction that then
becomes septic
The most common fungi to invade the brain are candida and Cryptococcus
Cryptococcal meningitis is a common opportunistic infection in HIV, and can be fatal within
weeks, or last years
o The meningitis can also lead to hydrocephalus
o There’s gelatinous material in the subarachnoid space, and small cysts in the
parenchyma called “soap bubbles”
Protozoa that infect the CNS include malaria, toxoplasmosis, amebas, and trypanosomes
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Cerebral toxoplasmosis is an opportunistic infection seen often in HIV
o Cerebral toxoplasmosis shows ring enhancing lesions on CT and MRI, but this isn’t
diagnostic because it’s seen in lymphomas, tuberculosis, and fungal infections too
o Toxoplasmosis of the CNS causes brain abscesses most often in the cerebral cortex, that
have the protozoa in them
Naegleria amebas cause a rapidly fatal necrotizing encephalitis
Prions – abnormal forms of cell proteins that cause transmissible neurodegenerative disorders
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Includes Creutzfeldt-Jakob disease, Gertsmann-Straussler-Scheinker syndrome, fatal familial
insomnia, and kuru
All of these disease have abnormal forms of prion protein (PrP), that is both infectious and
transmissible
These diseases are characterized by “spongiform change” caused by intracellular vacuoles in
neurons and glia, leading to progressive dementia
Normal PrP is a normal cell protein in neurons
o Disease happens when the PrP undergoes a conformation change from a normal α-helix
into a β-pleated sheet
o This shape change makes PrP resistant to digestion with proteases, and it accumulates
in neural tissue, leading to cytoplasmic vacuoles and neuron death
o The conformation change in PrP can happen spontaneously at a very low rate, or at a
high rate if it’s familial from mutation to gene PRNP
o PrP than causes conversion of other PrP’s into the pathogenic form, which is why it’s
considered infectious
The most common prion disease is Creutzfeldt-Jakob (CJD), and most cases are sporadic
o CJD is rare, and manifests as rapidly progressive dementia
 First there’s changes in memory and behavior, the rapid dementia, often with
involuntary jerking muscle contractions on sudden stimulation (startle
myoclonus)
o CJD is most common in people in their 70’s
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CJD is always fatal, and most don’t make it a year
The diagnostic finding is spongiform transformation fo the cerebral cortex, forming
vacuoles in the neuron cytoplasm
 There’s severe neuron loss and expansion of the vacuoles, with no
inflammation
Variant CJD (vCJD) – differs in that it happens in young adults, mainly causes behavior problems
early, and the syndrome progresses more slowly
o vCJD is characterized by extensive cortical plaques with a surrounding halo of
spongiform change
o vCJD is linked to spongiform encephalopathy in cows (bovine spongiform
encephalopathy)
fatal familial insomnia (FFI) – starts with sleep disturbances, and is caused by mutation to PRNP
o They then develop ataxia, autonomic issues, stupor, and finally coma
o There’s no spongiform pathology in FFI,a dn instead there’s lots of neuron loss and
reactive gliosis in the anterior ventral and dorsomedial nuclei fo the thalamus
Demyelinating diseases are acquired diseases that remove myelin and spare the axon
The medical problems are caused by the effect of myelin loss on conducting signals down the axon
Leukodystrophies - inherited disorders that affect making of myelin
Multiple sclerosis (MS) – autoimmune demyelinating disorder characterized by white matter lesions in
the CNS that cause neural problems
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MS is the most common demyelinating disorder
Onset usually is between childhood and age 50
Women get MS twice as often as men do
The most common form of MS has an episode of relapsing and remitting that can last weeks to
years, followed by gradual partial recovery of neurologic function
The lesions in MS are caused by an immune response against the myelin sheath
MS risk increases if a relative has it
o The DR2 haplotype of the MHC is often messed up when genetics cause MS
The autoimmunity of MS is caused by CD4+ TH1’s and TH17’s that react against self myelin
o TH1 release IFN-γ, which activates macrophage
o TH17 promote recruiting WBCs for inflammation
o These WBCs are the causes of the demyelination
o MS plaques are made of WBCs and macrophage
B cells may also be involved, since you see oligoclonal bands of IgG’s in CSF of people with MS
o Tells you there’s B cell clones there
MS plaques look glassy and gray-tan with well defined borders, in the white matter
o Active plaques show demyelination, and macrophage filled with lipids (myelin)
 The axon is preserved, but oligodendrocytes are hurt
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Inactive plaques show little to no myelin, and less oligodendroyctes
 They’re replaced by astrocytes proliferating, and gliosis
In MS you may see a small amount of remyelination, but not enough
Unilateral visual problems are a common initial manifestation of MS
o The optic nerve is often affected, called optic neuritis
o Only at most ½ of people with optic neuritis will develop MS
If MS gets the brainstem, you get CN problems, ataxia, nystagmus, and internuclear
opthalmoplegia from it affecting the medial longitudinal fasciucula
If MS gets the spinal cord, you get motor and sensory problems, and problems voluntarily
controlling the bladder
Neuromyelitis optica- bilateral optic neuritis, along with spinal cord demyelination
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Often show antibodies to aquaporins, which are needed in astrocytes to help maintain the
blood-brain barrier
Acute disseminated encephalomyelitis (ADEM) – demyelination seen after a viral infection, or rarely
immunization
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Symptoms are seen a week or two after infection, and include general signs like headache,
lethargy, and coma, instead of focal findings seen in MS
The disease progresses quickly, and 1/5 die, both those that don’t recover quickly
Unlike MS, all ADEM lesions look similar
Acute necrotizing hemorrhagic encephalomyelitis (ANHE) – CNS demyelination seen often in kids
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It’s preceded by an upper respiratory infection
Often fatal, and those that survive have problems
ANHE lesions look like ADEM, but much more severe, and include hemorrhage of blood vessels,
necrosis of gray and white matter, fibrin deposition, and lots of neutrophils
Central pontine myelinolysis – characterized by loss of myelin in the basis pontis and pontine
tegmentum
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Shows hyponatremia that quickly fixes itself, and quadriplegia
There will be myelin loss with no inflammation