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Gen Pathology (Dra.

Sionzon)

CNS PART 1 : CNS PATHOLOGY

16 February 2008

CNS PATHOLOGY

Review: Principal cells of the CNS


• Neurons
• Glial Cells
– Astrocytes
– Olidodendroglia
– ependyma
• Microglia
• Meningothelial cells

Notes:
negli bodies – in rabies
cytopathic efeects – in CMV
neurofibrillary bundles – in alzheimers

1. ASTROCYTES
• star-shaped glial cells
• functions include nutritional supply and insulation of
neurons, contribution to blood brain barrier
• play prominent role in response to injury
• cytoplasm of “resting” astrocytes not readily evident
• response to tissue injury: hyperplasia and
hypertrophy; astrogliosis
• highlighted by immunostaining for GFAP (Glial fibrillary
Astrocytic protein –for astrocytic process)
Acute neuronal injury (red neurons): irreversible injury due
to various causes including hypoxia/ischemia, infections, toxins

(a) (b)
(a) ASTROGLIOSIS (GLIOSIS)
(b) GFAP STAINING OF REACTIVE ASTROCYTES
Chromatolysis: reaction w/in the neuronal cell body to axonal
injury
2. OLIGODENDROCYTES
• Process wrap around axons of neurons to form myelin
• Oligodendrocyte injury is a feature of demyelinating
diseases (e.g multiple sclerosis)
• Nuclei may harbor viral inclusions in progressive
multifocal leukoencephalopathy
• Limited capacity for regeneration

brim, leu, virns 1 of 10


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• Cerebral parenchymal compartment


• Intravntricular spaces

Notes: egg shaped daw

3. EPENDYMAL CELLS
• Line ventricular chambers, aqueduct, central canal of
spinal cord
• Modulate the transfer of fluid between CSF and
parenchyma
• Reaction to injury ; ependymal granulations (loss of
ependyma plus subependymal astrogliosis)

FEATURES UNIQUE TO CNS


• Enclosed in a rigid bony compartment
• Autoregulation of cerebral blood flow
• Dependent on glucose and high O2 supply
• CSF fills ventricles and spaces
• Lack a lymphatic circulation
• Cell have limited regenrative ability
• Immunologically secluded
• BBB and blood CSF barrier separates the brain from
the rest of the body

INTRACRANIAL COMPARTMENTS
• Epidural space
• Subdural space
• Subarachnoid space
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PATHOLOGIC REACTIONS
• Selective vulnerability”
• Pathologic reactions of neurons
– Acute injury
– Degeneration
– Axonal reaction
– Formation of neuronal inclusions
– Vacuolization of cytoplasm and neurophil
– Aggregation of abnormal proteins
– Neuronophagia
• Astrocytes - Gliosis – glial scar
• Microglia - glial nodules
– Phagocytosis of dying neurons
(neuronophagia)

COMMON PATHOPHYSIOLOGIC PHENOMENA

• Brain surrounded by rigid skull


A. CEREBRAL EDEMA • Rigid barriers divide the cranial cavity into
subcompartments (falx cerebri, cerebellar tentorium)
1. Vasogenic Edema • Intracranial volume is fixed (brain parenchyma, CSF,
– blood brain barrier dysfunction, fluid
blood)
accumulates between neurons and glial cells
2. Cytotoxic Edema • Space occupying masses (tumor, hemorrhage, etc),
– fluid accumulates inside the cells (ischemia, brain edema, increased CSF
CSF lead to increased
hypoxia) intracranial pressure and may cause herniation
• Herniation is displacement of expanding brain to
3. Interstitial Edema adjacent subcompartments or through formaen
– results from increase CSF (dysfunction of magnum
brain CSF barrier)
– Complication of hydrocephalus COMPLICATIONS OF BRAIN HERNIATION
Gross Appearance Of The Brain In Vasogenic Edema • Necrosis of herniated parenchyma
• Common autopsy findings • Compression of vessels and consequent
– Flattened broad gyri infarction (eg posterior cerebral artery infarction
– Narrowed slit-like sulci involving the visual cortex)
– Compressed lateral ventricles
– Brain is heavier than normal, soft; fluid seeps
• Nerve compression (eg III cranial nerve in
from cut surfaces transtentorial herniation w/ consequent papillary
– Signs of herniation may be seen dilation and impaired ocular movement)
• Death (eg brainstem compression in tonsillar
herniation

MALFORMATIONS AND DEVELOPMENTAL DEFECTS

A. DEVELOPMENTAL DISORDERS
1. Cranial Dysraphism
– Anencephaly
– Encephalocele
2. Spinal Dysraphism
– Spina bifida occulta
– Meningocele
– Meningimyelocele
B. HERNIATIONS – Rachischisis
1. Cingulate Herniation/ Subfalcine
– Cingulate gyrus compressed underneath the B. CNS MALFORMATIONS
falx cerebri
– Caused by unilateral hemispheric mass
• Congenital CNS Malformation : Morphological CNS
defect present at birth due to an abnormal
2. Transtentorial Herniation/ Uncinate development process)
– Uncus gyri herniate in the cerebellar
tentorium • Causes: unknown in a majority of cases, genetic and
chromosomal abnormalities, environmental (eg
3. Tonsillar Herniation infection, drugd, nutritional, multifactorial)
– Cerebellar tonsils are compressed in the
• Anatomic pattern of malformation reflects the stage of
foramen magnum
formation of the CNS at the time of injury
– Life threatening
Important types and examples:
1. Neural Tube Defects (eg anencephaly,
myelomeningocele, spina bifida, encephalocele)
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2. Forebrain anomalies (eg holoprosencephaly, 2. NEURAL TUBE DEFECTS


agenesis of the corpus callosum, neuronal migration • Transformation of the neural plate into the neural tube
defects, microencephaly) occurs at 22-28 days of gestation
• Neural tube defects are due to failure of a portion of
3. Posterior fossa defects (Arnold-Chiari and Dandy-
the neural tube to close or reopening of a region after
Walker malformation)
successful closure
4. Hydromyelia, syringomyelia
• All characterized by abnormalities involving both
neural tissue and overlying one or soft tissues
1.
• Most common type of CNS malformation, wide
geographic and ethnic variation in frequency,
recurrence rate: 4-5%
• Etiology: unknown,
unknown, some association w/
chromosomal disorders (trisomy 13), environmental
factors (eg folate deficiency), interaction of genetic
and environmental etiology suspected based on
research in mice.

Anenephaly with complete rachischisis (craniorachischisis)


: Skull vault and vertebral arches are deficient, replacement of
brain w/ vascular mass (area cerebrovasculosa)

Spinal neural tube defects:


Myelomeningocele: herniation of the spinal cord and
meningeal tissue through a vertebral defect (picture)
Meningocele: herniation of meningeal tissue only
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Encephalocele (occipital) : herniation of brain tissue


through a skull defect
3. FOREBRAIN ANOMALY

FOREBRAIN ANOMALY

Forebrain anomaly: Holoprosencephaly


• Failure of separation of cerebral hemispheres
• May be associated with facial abnormalities (eg Agyria Polymicrogyria
cyclopia)
• Etiology associations: 4. POSTERIOR FOSSA ABNORMALITY: Arnold- Chiari
o trisomy 13, 18 Malformation (Chiari Type II Malformation)
o Sonic hedgehog gene mutations • Small posterior fossa
o Maternal diabetes mellitus • Downward extension of cerebellar vermis through
o Toxoplasmosis, other infections foramen magnum
• Caudally displaced medulla
• Often associated;
o Aqueductal stenosis
o Hydrocephalus
o Lumbar myelomeningocele
o hydromyelia

Forebrain anomaly: Agenesis of the corpus callosum


• Absence of white matter bundles connecting cerebral
PERINATAL BRAIN INJURY
hemispheres

• Important cause of childhood neurological disability


• Cerebral Palsy (a clinical term): non-progressive
neurologic motor deficit attributable to insults
occurring during the prenatal and perinatal period
• Most common underlying pathology : hemorrhages
and infarctions
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• Premature infants at increased risk germinal matrix


hemorrhage and periventricular infarcts leading to
periventricular leucomalacia
• In term infants: choroid plexus hemorrhage and
infarcts involving cerebral cortex, basal ganglia and
thalamus
• Common causes: maternal disease (eg hemorrhage,
shock, drugs, trauma), placental abnormalities,
neonatal disease (eg congenital heart disease)

Caseous mycobacterial tubercles in the subarachnois space

GERMINAL MATRIX HEMORRHAGE in premature infant

TRAUMA

A. PHYSICAL INJURIES
• Contusions (bruising)
– “Coup lesions” and “contre coup” contusion Discharge of mycobacteria from tubercles into the
– Rapid accelaration/ deceleration subarachnoid space results in tuberculous meningitis that
• Laceration (tearing) typically affects the base of the brain.
• Diffuse Axonal Injury
• Traumatic vascular injury
• Penetrating wounds

B. SPINAL CORD INJURIES


• Hyperextension injury
– Cervical spinal
– Sudden posterior displacement of the head
– Rupture of anterior spinal ligament
• Hyperflexion injury
– Impact force driving the head down and
forward
– Anterior contusion of the cervical spine

C. INTRACRANIAL BLEEDING
Tuberculous meningitis – microscopic findings:
• Epidural hematoma
granulomatous inflammation w/ multinucleated giant cells,
• Subdural hematoma
epithelioid cells, macrophages and lymphocytes.
• Subarachnoid hematoma
• Intracerebral hemorrhage
• Intraventricular hemorrhage “hydrocephalus
internus”

INFECTIONS

A. CHRONIC BACTERIAL INFECTIONS - TUBERCULOSIS


• Manifestations: chronic mengitis and circumscribed
abscess: TUBERCULOMA
• Typically due to hematogenous spread of bacteria
from pulmonary lesions or lymph nodes
• This leads to caseous tubercles in the subarachnoid
space or brain parenchyma
Tuberculoma: Growth or coalescence of small parenchymal
tubercles creates abscesses w/ a caseous center. May occur
anywhere in the brain but show a predilection for the
cerebellum
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• Impaired joint position sense, ataxia


B. CHRONIC BACTERIAL INFECTIONS -NEUROSYPHILIS • Loss of pain sensation- skin and joint damage
• Neurosyphylis is a tertiary stage of syphilis and • Lightning pains
occurs in about 10% of patients w/ untreated infection • Loss of deep tendon reflexes
• Manifestations: meningeal- meningovascular syphilis,
paretic neurosyphilis, tabes dorsalis C. VIRA
VIRAL INFECTIONS ; VIRAL ASEPTIC MENINGITIS
• Meningeal- Meningovascular Syphilis : chronic • Most common viral infection of the CNS
mengitis w/ numerous plasma cellS that may be • Common causative agents : enteroviruses, herpes
associated w/ obliterative endarteritis simplex virus type 2, mumps virus
• Paretic Neurosyphilis ; invasion of the brain by • Pathology : mild to moderate lymphocytic infiltration
Treponema pallidum inflammatory meningeal lesions of the leptomeninges
are associated w/ parenchymal damage : loss of • Clinical symptoms: headache, fever, usually short,
cortical neurons, striking proliferation of microglia (rod benign course
cells)

D. VIRAL ENCEPHALITIS, MYELITIS,


ENCEPHALOMYELITIS
• Viral infections of the brain (encephalitis), spinal cord
(myelitis) or both (encephalomyelitis)
• Clinically most important infections caused by HIV,
Herpes Simplex Virus, Human Cytomegalovirus,
Poliovirus, Rabies Virus, Measles Virus. JC Virus,
Arboviruses
• Localization of the infection within the CNS is often
characteristic for specific viruses
• Microscopic pathology similar for almost all:
perivascular cuffs of the lymphocytes, astrogliosis,
microglial nodules, if neurons are infected:
neuronophagia
• Viral inclusions in some cases may be characteristic

Neurosyphilis : leptomeningeal thickening, spirochetes and


rod cells. Patients show progressive loss of mental functions,
often delusions of grandeur terminating in severe
dementia:
dementia: general paresis of the insane

E. HIV ENCEPHALITIS
• As many as 60% of patients w/ AIDS develop
neurological dysfunction
• HIV infection can cause CNS damage by infecting the
CNS and by leading to opportunistic CNS infections
• Main target cells of HIV in CNS : microglial cells and
macrophages
• Cytokines and reactive oxygen and nitrogen species
released from infected cells may cause secondary
neuron damage and lead to HIV dementia
Tabes dorsalis. Degeneration of the posterior columns of the • Typically affects deep gray structures and white
spinal cord w/ loss of both axons and myelin matter
Symptoms:
• Multinucleated cells, microglial nodules, demyelination
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• Most common opportunistic CNS infections in AIDS:


CMV Encephalitis, Toxoplasma Abscess, JC Virus –
Induced Progressive Multifocal Leukoencephalopathy

F. HERPES SIMPLEX ENCEPHALITIS


• Most common sporadic encephalitis in the US, affects
immunocompetent people, most commonly due to
HSV-1 CMV Ventriculoencephalitis in AIDS:
AIDS: Virus targets
• Initial infection of mucocutaneous surfaces of oral ependyma and subependymal brain parenchyma. Note
cavity, nose, eye cytomegalic cells w/ intranuclear inclusions
• Virus infects nerve endings, reaches ganglia in the H. FUNGAL INFECTIONS OF THE CNS
peripheral nervous system and the CNS by axonal • Affect primarily immunocompromised patients in
transport = in most cases causes latent infection in
industrialized countries
neurons
• Often presents as a component of widespread
• Initial infection and reactivation from neurons may
hematogenous dissemination of fungus
cause encephalitis
• Three basic patterns : Vasculitis, Chronic
• HSV encephalitis typically involves the temporal lobe
Meningitis, And Parenchymal Invasion
(granulomas or abscesses)
G. CYTOMEGALOVIRUS INFECTION OF THE CNS
• Vasculitis commonly caused by Aspergillus and Mucor,
• CMV infection of the CNS occurs in two groups of occasionally Candida
individuals : fetuses and the immunocompressed
• Congenital CMV infection l: the commonest of the
known intrauterine viral infections affecting 0.2-2.2%
of live births
• Acute infection: Necrotzing Encephalitis
• Residual lesions : microcephaly, polymicrogyria,
hydrocephalus and periventricular calcifications

Mucormycosis: CNS vasculitis following local brain invasion


from a paranasal sinus in a diabetic patient w/ ketoacidosis.

Residual lesions of congenital CMV infection: periventricular


calcifications and hydrocephalus
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ASPERGILLOSIS

Candida Albicans Infection most often associated with


microabscesses but may also cause vasculitis leading to
multiple hemorrhagic infarcts
TOXOPLASMOSIS
FUNGAL INFECTIONS
• Fungi causing chronic mengitis: Histoplasma DISEASE OF MYELIN
capsulatum, Coccidioides immitis, Blastomyces
dermatitidis, Cryptococcus neoformans • Diseases in w/c myelin is lost selectively w/ relative
• Cryptococcal mengitis : observed in increased preservation of other neural structures including
frequency in AIDS patients axons
• Two main categories:
VIII 1. associated w/ abnormal myelin metabolism:
Leukodystrophies
VIII 2. associated w/ loss of normal myelin :
Demyelinating diseases most common : multiple
clerosis
• LEUKODYSTROPHIES : inherited diseases, typical
onset in infancy to adolescence, diffuse white matter
involvement, relentless progressive course
• MULTIPLE SCLEROSIS sporadic incidence, typical
onset in 20’s and 30’s, multiple demyelinating foci at
different times during disease course, waxing and
Cryptococcus Meningitis: multiple small cysts in the basal waning course
ganglia corresponding to aggregates of fungi within expanded
perivascular (Virchow-robin) spaces with minimal associated MULTIPLE SCLEROSIS
inflammation • Clinical : distinct episodes of neurological deficits
attributable to white matter lesions “ separated in
I. PROTOZOAL CNS INFECTION: TOXOPLASMOSIS
time and space “, waxing and waning course
• Similarly to CMV, important cause of congenital
infections and necrotizing encephalitis in the • Common symptoms : impaired vision, motor
immunocompromised weakness, paresthesias, ataxia, etc.
• Congenital toxoplasma infection is responsible for • Gross pathology;
pathology; multiple, well delineated, firm,
the classic triad of : Chorioretinitis, Cerebral gray lesions (plaques) in white matter, may focally
Calcifications And Hydrocephalus extend into gray matter
• In immunocompromised patients toxoplasma causes • Microscopic pathology : well defined area of myelin
solitary or multifocal abscesses loss with relative preservation of axons, lymphocytic
• Up to 30% of AIDS patients affected infiltrate, loss of oligodendrocytes, foamy
macrophages, astrogliosis
• Shadow plaque : only partial loss of myelin
Gen Pathology – CNS1: CNS Pathology by Dra Sionzon Page 10 of 10

guys, di na ko gumawa ng low ink version ha. kasi sabi ni doc


kelngan daw yung pictures.. so ayan. magsayang na tayo ng
ink! wohoo!!!!... eto pla e yung ppt lang. I checked the buk,
dami pla niang di diniscuss.. Mga impt notes lang to.. so kahit
mganda tong trans pagkagawa ko, don’t rely on this..lam ko
namang masisipag kayo e. may medstudent bang tamad?!
Kung tamad ka edi sna wla ka na ditto.. diba?!.. in short, read
your books.. haha! ;) –brim