Nontumoral

Central Nervous System

Pathology

DULCE ANN ROSS B. DALANGIN, MD, DPSP

 CEREBROSPINAL FLUID
• The choroid plexus within the ventricular
system produces CSF, which normally
circulates through the ventricular system
and enters the cisterna magna at the
base of the brainstem through the
foramina of Luschka and Magendie.
• Subarachnoid CSF bathes the superior
cerebral convexities and is absorbed by
the arachnoid granulations.
 HYDROCEPHALUS
• Accumulation of excessive CSF within the
ventricular system
• Most cases of hydrocephalus are a consequence of
impaired flow and resorption of CSF
• Overproduction is a rare cause that can
accompany tumors of the choroid plexus.
• In all forms, the increased volume of CSF expands
the ventricles and can elevate the intracranial
pressure.
 HYDROCEPHALUS
• Noncommunicating (obstructive) - If
the ventricular system is only focally
obstructed, due to a mass in the third
ventricle or to aqueductal stenosis
• Communicating hydrocephalus - the
ventricular system remains in continuity
with the subarachnoid space and there is
enlargement of the entire ventricular
system; causes include overproduction of
CSF from a choroid plexus tumor and
arachnoid fibrosis following meningitis.
• Hydrocephalus ex vacuo – a
compensatory increase in ventricular
volume secondary to a loss of brain
parenchyma.
Dural Folds
 HERNIATION
• The displacement of brain tissue past rigid dural
folds (the falx and tentorium) or through
openings in the skull because of increased
intracranial pressure.
• As the volume of the brain increases, CSF is
displaced, leading to increasing pressure within the
cranial cavity
• Herniation occurs when this pressure exceeds the
brain’s limited capacity to accommodate the
increased intracranial pressure.
• Brain herniation is mostly caused by mass effects,
either diffuse (generalized brain edema) or focal
(tumors, abscesses, or hemorrhages).
 HERNIATION
• Subfalcine (cingulate) herniation - unilateral or
asymmetric expansion of a cerebral hemisphere
displaces the cingulate gyrus under the falx.

- May lead to compression of the anterior cerebral

artery and its branches, resulting in secondary
infarcts.
• Tonsillar herniation - displacement of the
cerebellar tonsils through the foramen magnum

- Life-threatening because it causes brainstem

compression and compromises vital respiratory and
cardiac centers in the medulla.
 HERNIATION
• Transtentorial (uncal, mesial temporal) herniation - the
medial aspect of the temporal lobe is compressed against the
free margin of the tentorium. With increasing displacement of
the temporal lobe, the third cranial nerve is compromised,
resulting in pupillary dilation and impaired ocular movements on
the side of the lesion. The posterior cerebral artery may also be
compressed, resulting in an infarct of its territory (which
includes the primary visual cortex). When the extent of
herniation is large enough, the contralateral cerebral peduncle
may be compressed, resulting in hemiparesis ipsilateral to the
side of the herniation. Progression of transtentorial herniation is
often accompanied by secondary hemorrhagic lesions in the
midbrain and pons, termed Duret hemorrhages. These linear or
flame-shaped lesions usually occur in the midline and
paramedian regions and are believed to be due to distortion or
tearing of penetrating veins and arteries supplying the upper
brainstem.
Neural Tube Defects
• Midlinemalformations that involve some
combination of neural tissue, meninges, and
overlying bone or soft tissue
 Anencephaly
 Myelomeningocele
 Encephalocele
 Spinal dysraphism or spina bifida
 ANENCEPHALY
• A malformation of the anterior end of
the neural tube that leads to absence
of most of the brain and calvarium.
• Forebrain development is disrupted at
approximately 28 days of gestation,
and all that remains in its place is the
area cerebrovasculosa, a flattened
remnant of disorganized brain tissue
with admixed ependyma, choroid
plexus, and meningothelial cells.
MYELOMENINGOCELE
• Extension of CNS tissue through a defect in the
vertebral column
• Meningocele - there is only a meningeal extrusion.
• Myelomeningoceles occur most commonly in the
lumbosacral region.
• Affected individuals have motor and sensory deficits in
the lower extremities as well as disturbances of bowel
and bladder control.
• Often complicated by superimposed infection of the
cord due to defective barrier function of the thin,
overlying skin.
 ENCEPHALOCELE
• An extrusion of malformed brain
tissue through a midline defect
in the cranium.
• Most often occurs in the
occiput, although nasofrontal
variants involving the orbit,
ethmoid, or cribriform plate
(sometimes misleadingly
referred to as a “nasal glioma”)
also are seen.
Spinal dysraphism or spina bifida
• The most common neural tube defects
• May be an asymptomatic bony defect (spina bifida occulta) or a
severe malformation with a flattened, disorganized segment of
spinal cord, associated with an overlying meningeal outpouching.
MENINGES
 EPIDURAL HEMATOMA
• The dura is fused with the periosteum and is supplied
by a number of dural arteries. These arteries, most
notably the middle meningeal artery, are vulnerable
to traumatic injury.
• In adults, this most often occurs with temporal skull
fractures in which the fracture crosses the course of the
vessel.
• In children, in whom the skull is deformable, a
temporary displacement of the skull bones leading to
laceration of a vessel can occur in the absence of a
skull fracture.
• Once a vessel has been torn, the extravasation of blood
under arterial pressure can cause the dura to separate
from the periosteum, creating a space.
 EPIDURAL HEMATOMA
• The expanding hematoma compresses the
underlying brain.
• When blood accumulates slowly, patients may
experience a lucid period before the onset of
neurologic signs.
• A symptomatic epidural hematoma is a
neurosurgical emergency; without prompt
diagnosis and drainage, fatal brain herniation
may occur within a few hours.
SUBDURAL HEMATOMA

• The dura is composed of two layers—an external

collagenous layer and an inner more cellular layer
containing fibroblasts.
• Bridging veins travel from the convexities of the
cerebral hemispheres through the subarachnoid
space and dura to empty into the dural sinuses.
The brain is suspended in CSF, but the venous
sinuses are fixed relative to the dura; as a result,
traumatic displacement of the brain can tear the
veins at the point where they penetrate the dura.
SUBDURAL HEMATOMA
• The extravasated blood dissects through the
two layers of the dura, producing a subdural
hematoma.
• In older individuals with brain atrophy, the
bridging veins are stretched, hence the
increasing incidence of subdural hematoma
with aging.
• Infants are also very susceptible to subdural
hematomas because their bridging veins are
thin-walled.
CEREBROVASCULAR DISEAES
• injury to the brain as a consequence of altered blood flow
• Can be grouped into ischemic and hemorrhagic etiologies, with
tissue infarction the ultimate consequence of both.
• “Stroke” is the clinical designation
 Neurologic signs and symptoms that can be explained by a vascular
mechanism, have an acute onset, and persist beyond 24 hours.

• If symptoms disappear within 24 hours, the event is termed

“transient ischemic event.”
STROKE MECHANISMS
• Ischemia and/or hypoxia resulting from
impairment of blood supply and oxygenation of CNS
tissue. This can be either a global or focal process,
with the clinical manifestations determined by the
region of brain affected. In the brain, embolism is a
more common cause of vascular occlusion than
thrombosis.
• Hemorrhage resulting from rupture of CNS vessels.
Common etiologies include hypertension and
vascular anomalies (aneurysms and malformations).
Intracranial Hemorrhage
• Intraparenchymal hemorrhage
• Subarachnoid hemorrhage and ruptured saccular
aneurysm
• Vascular malformations
Intraparenchymal
Hemorrhage
• Rupture of a small intraparenchymal vessel can result
in a primary hemorrhage within the brain, often
associated with sudden onset of neurologic symptoms
(stroke)
• Should not be confused with the secondary
hemorrhagic transformation of an occlusive infarct
• Hypertension is the risk factor most commonly
associated with deep brain parenchymal hemorrhages,
accounting for more than 50% of clinically significant
hemorrhages and for roughly 15% of deaths among
individuals with chronic hypertension.
Subarachnoid Hemorrhage and
Ruptured Saccular Aneurysm
• The most frequent cause of spontaneous subarachnoid
hemorrhage is rupture of a saccular (“berry”) aneurysm
in a cerebral artery.
• Saccular aneurysm is the most common type of
intracranial aneurysm
• Other aneurysm types include atherosclerotic (fusiform;
mostly of the basilar artery), mycotic, traumatic, and
dissecting. These latter three, like saccular aneurysms,
are most often found in the anterior circulation, but more
often cause cerebral infarction rather than subarachnoid
hemorrhage.
Subarachnoid Hemorrhage
and Ruptured Saccular
Aneurysm
Saccular Aneurysm

• The structural abnormality of the involved vessel (absence of smooth

muscle and intimal elastic lamina) suggests that they are
developmental anomalies.
Ruptured Aneurysm
• Most frequent in the fifth decade
• More frequent in women
• Aneurysms rupture at a rate of 1.3% per year, but the risk is higher for
larger aneurysms
• Aneurysms greater than 10 mm in diameter have a roughly 50% risk of
bleeding per year.
• Rupture may occur at any time, but in about one-third of cases it is
associated with acute increases in intracranial pressure, such as with
straining at stool or sexual orgasm.
• Blood under arterial pressure is forced into the subarachnoid space, and
affected individuals are stricken with a sudden, excruciating headache
(“the worst headache I’ve ever had”) and rapidly lose consciousness.
• Between 25% and 50% of patients die with the first rupture, but patients
who survive often improve and recover consciousness in minutes.
 Vascular Malformations
• Classified into arteriovenous malformations,
cavernous malformations, capillary telangiectasias,
and venous angiomas.
• The first two are the types associated with risk of
hemorrhage and development of neurologic
symptoms.
• Arteriovenous malformations are frequently
associated with activating somatic mutations in the
KRAS oncogene within the endothelial cells that
line the malformed vessels.
MENINGITIS
• An inflammatory process of the leptomeninges and CSF within the
subarachnoid space, usually caused by an infection.
• Meningoencephalitis refers to inflammation of the meninges and
brain parenchyma.
• This reaction may also occur in response to a nonbacterial irritant
introduced into the subarachnoid space (chemical meningitis) or in
the context of a systemic autoimmune disease.
• Infectious meningitis is broadly classified into acute pyogenic
(usually bacterial), aseptic (usually acute or subacute viral), and
chronic (usually tuberculous, spirochetal, or cryptococcal).
 Acute Pyogenic (Bacterial) Meningitis
• Neonate - Escherichia coli and group B streptococci
• Elderly - Streptococcus pneumoniae and Listeria
monocytogenes
• adolescents and young adults - Neisseria meningitidis
• An exudate is evident within the leptomeninges over the
surface of the brain
• The meningeal vessels are engorged and stand out
prominently.
• Anatomic distribution of the exudate:
 H. influenzae meningitis - basal
 Pneumococcal - densest over the cerebral convexities near the
sagittal sinus
 Brain Abscess
• A localized focus of necrosis of brain tissue with
accompanying inflammation, usually caused by a
bacterial infection.
• May arise by direct implantation of organisms, local
extension from adjacent spread (usually from a primary
site in the heart, lungs, or bones of the extremities, or
secondary to bacteremia from dental procedures).
• Predisposing conditions: acute bacterial endocarditis,
which may give rise to multiple brain abscesses;
congenital heart disease with right-to-left shunting and
loss of pulmonary filtration of organisms; chronic
pulmonary sepsis, as in bronchiectasis; and systemic
disease with immunosuppression.
• Streptococci and staphylococci
 Rabies Virus

• Rabies is severe encephalitis transmitted to humans by

the bite of a rabid animal, usually a dog or various wild
mammals that are natural reservoirs. Exposure to
certain species of bats, even without a known bite, can
also lead to rabies.
• Widespread neuronal degeneration and an
inflammatory reaction that is most severe in the
brainstem;
• Negri bodies, the pathognomonic microscopic finding,
are cytoplasmic, round to oval, eosinophilic inclusions
found in pyramidal neurons of the hippocampus and
Purkinje cells of the cerebellum, sites usually devoid of
inflammation.
• Rabies virus can be detected within Negri bodies by
ultrastructural and immunohistochemical methods.
 PRION DISEASE

• Rapidly progressive neurodegenerative disorders caused by

aggregation and intercellular spread of a misfolded prion protein (PrP)
• May be sporadic, familial, or transmitted
• Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome,
fatal familial insomnia, and kuru in humans
• Scrapie in sheep and goats
• mink-transmissible encephalopathy
• chronic wasting disease of deer and elk
• bovine spongiform encephalopathy
• Exemplify degenerative disorders that are caused by “spreading” of misfolded
proteins that allows a pathogenic protein to acquire some of the characteristics
of an infectious organism.
PRION DISEASE
• Normal PrP is a 30-kD cytoplasmic protein of unknown function.
• Disease occurs when PrP undergoes a conformational change from its
normal α-helix–containing isoform (PrPc) to an abnormal β-pleated
sheet isoform, usually termed PrPsc (for scrapie); associated with this
conformational change, PrP acquires resistance to digestion with
proteases, such as proteinase K.
• Accumulation of PrPsc in neural tissue seems to be the cause of the
pathologic changes in these diseases
• How this material induces the development of cytoplasmic vacuoles
and eventual neuronal death is still unknown.
• Immunostaining for PrP after partial digestion with proteinase K allows
detection of PrPsc, which is diagnostic.
“Spongiform change” caused by intracellular vacuoles in neurons and
glia, and clinically by a rapidly progressive dementia.
 Alzheimer Disease
• Most common cause of dementia in older adults, with an increasing incidence
as a function of age.
• Becomes clinically apparent as insidious impairment of higher cognitive functions.
• As the disease progresses, deficits in memory, visuospatial orientation, judgment,
personality, and language gradually emerge
• Over a course of 5 to 10 years, the affected individual becomes profoundly disabled,
mute, and immobile.
• The incidence of the disease increases with age, and the prevalence roughly doubles
every 5 years, starting from a level of 1% for the 60- to 64-year-old population and
reaching 40% or more for the 85- to 89-year-old cohort.
• About 5% to 10% of cases are familial
• Although pathologic examination of brain tissue obtained at autopsy remains necessary
for definitive diagnosis of AD, the combination of clinical assessment and current
radiologic methods allows accurate premortem diagnosis in 80% to 90% of cases.
 Alzheimer Disease
• Fundamental abnormality: accumulation of two proteins
(Aβ and tau) in specific brain regions, likely as a result of
excessive production and defective removal
• Two pathologic hallmarks: amyloid plaques and
neurofibrillary tangles.
• Plaques are deposits of aggregated Aβ peptides in the
neuropil, while tangles are aggregates of the microtubule
binding protein tau, which develop intracellularly and
then persist extracellularly after neuronal death.
• Both plaques and tangles appear to contribute to the
neural dysfunction, and the interplay between the
processes that lead to the accumulation of these two
types of abnormal protein aggregates is a critically
important aspect of AD pathogenesis.
Ethanol
• The effects of acute ethanol intoxication are reversible
• Chronic alcohol abuse is associated with a variety of
neurologic sequelae, including Wernicke-Korsakoff
syndrome from thiamine deficiency.
• Cerebellar dysfunction occurs in about 1% of chronic
alcoholics, and is associated with a clinical syndrome of
truncal ataxia, unsteady gait, and nystagmus.
• Histologic changes: atrophy and loss of granule cells,
predominantly in the superior anterior vermis.
• In advanced cases, there is loss of Purkinje cells and
proliferation of the adjacent astrocytes (Bergmann gliosis)
between the depleted granular cell layer and the
molecular layer of the cerebellum.
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