Pathology of the Central Nervous System Lecture by Dr. Galvan SBCM2016
SBCM2A2016
Structure and function
Congenital diseases
Infections
Traumatic
Vascular
Degenerative
Toxic and metabolic
Ischemia
Neoplasms of CNS and PNS
CNS-UNIQUE FEATURES:
Surrounded by rigid structure
Regulated blood circulation and metabolic requirements
Absence of lymphatics
CSF circulation
Limited immunologic surveillance
Unique response of injury and wound healing
STRUCTURES:
Cerebral hemispheres
Brain stem
Cerebellum
Spinal cord
NEURONS
Functional roles
Distribution of their connections
Neurotransmitter used
Metabolic requirements
Level of electrical activity
Apoptopic mechanisms
Present in gray matter
Arranged as nucleus,ganglion or layered cortex
Non-mitotic
Very sensitive to hypoxia/ glycemia (
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- Owls eye onclusion on nucleus and cytoplasm
5. Degenerations/ degenerative disease
Neuronal intracytoplasmic inclusions
- Neurofibrillary tangles
- Lewy bodies
- Vacuolations of perikaryon and neuronal processes
- In the neuropil
GLIA-SUPPORT
Glia means glue
1. Astrocytes 2. Oligodendrial cells 3. Microglial cells 4. ependymal cells
1. Astrocytes
Principal cell in repair and scar formation in the CNS
Act as metabolic buffers and detoxifiers
Have multipolar,branching cytoplasmic processes that emanate from the
cell body and contains GFAP
Contribute to barrier functions controlling the flow of macromolecules
between blood, CSF and brain.
Astrocytosis/ gliosis- hypertrophy and hyperplasia of astrocytes
Morphologic features:
Nuclei become enlarge, vesicular with prominent nucleoli
Cytoplasm becomes bright pink, irregular swath around an eccentric nucleus
which emerge stout ramifying processes (Gemistocytotic Astrocytes)
Cytoplasmic swelling
Alzheimer type II astrocyte- long standing hyperammonemia
Cytoplasmic inclusion bodies:
Rosenthal fibers
o Long standing gliosis
o Pilocytic astrocytoma
o Alexander disease
Corpora amylacea/polyglucosan bodies
Lafora bodies
2. Oligodendroglia
Responsible for CNS myelination
White matter disease
Demyelination-loss of myelin with rerlative preservation of axon
Involved in inflammatory,infectious, and metabolic diseases
Reactions of Oligodendroglial cells:
Injury/apoptosis- feature of acquired demyelinating disorders and
leukodystrophies
Nuclei viral inclusions- progressive multifocal leukoencephalopathy
Glial cytoplasmic inclusions- multiple system atrophy
3. Microglia
Derived from hematogenous mononuclear phagocytes
Functions as brain histiocyte/macrophage
Prominent in viral infections of CNS
Reactions of Microglia to Injury:
Proliferation
Developing elongated nuclei (rod cells)
Forming aggregates small foci of tissue necrosis (microglial nodules)
Congregating around cell bodies of dying neurons (neuronophagia)
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Reactions of Ependymal cells:
Do not have specific patterns of reactions
Ependymal granulations
- Inflammation or dilatation of ventricular system, disruption of
ependymal lining with proliferation of subependymal astrocyte
proliferation
Viral inclusions
Ependymal Granulation
EDEMA, HERNIATION AND HYDROCEPHALUS The brain and spinal cord exist within a rigid compartment
Nerves and blood vessels pass through this structure via specific foramina
Advantage of housing the delicate CNS within a protective environment
Rigid compartment provide little room for brain parenchymal expansion
CEREBRAL EDEMA The accumulation of excess fluid within the brain parenchyma
Distinguished from hydrocephalus
- An increase in CSF volume within all or part of the ventricular system
Two underlying mechanisms for the development of cerebral edema:
1. Vasogenic edema
Integrity of the normal blood-brain barrier is disrupted
With increased vascular permeability, fluid shifts from the vascular
compartment into the intercellular spaces of the brain
Can be either localized- because of the abnormal permeability of vessels
adjacent to inflammation or tumors or generalized.
2. Cytotoxic edema
Increase in intracellular fluid secondary to neuronal, glial, or endothelial cell
membraine injury
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Generalized hypoxic/ ischemic insult or exposure to some toxins
3. Interstitial edema- transudation of CSF from ventricles to brain substance
Cerebral edema
HYDROCEPHALUS Impaired RESORPTION
Increased PRODUCTION
OBSTRUCTION
COMMUNICATING (entire)
NON-COMMUNICATING (part)
HIGH pressure
NORMAL pressure
1. NONCOMMUNICATING TYPE
Block in CSF flow within ventricular system e.g. aqueductal stenosis
Only a portion of the ventricular system is enlarged
2. COMMUNICATING TYPE
Obstruction in the subarachnoid space or CSF absorption
Enlargement of the entire ventricular system
Hydrocephalus ex vacuo- dilatation of the ventricular system with a compensatory
increase in CSF volume secondary to loss of brain parenchyma
BRAIN HERNIATION Intracranial pressure determined by:
Brain tissue
Blood
CSF
Expanding intracranial contents lead to:
Increased ICP
Decreased cerebral blood flow
BRAIN HERNIATION
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Rigid structures surrounding the brain:
Skull
Tentorium cerebella
Falx cerebri
Types of herniation:
1. Transtentorial/uncal herniation
2. Tonsillar Herniation
3. Subfalcine herniation
1. UNCAL/ TRANSTENTORIAL HERNIATION
Uncus/hippocampus herniates
Tentorium- rigid structure
Midbrain compression- decrease sensorium
CN III compression- papillary dilation and impairment of ocular movements
on the side of the lesion (blown pupil)
Kernohan notch- ipsilateral compression of cerebral peduncle on tentorium
Transtentorial (uncinate) herniation occurs when the medial aspect of the temporal lobe is compressed against the free margin of the tentorium
As the temporal lobe is displaced, the third cranial nerve is compromised, resulting in papillary dilation and impairment of ocular movements on the side of the lesion (blown pupil)
Kernohans notch is the term used for the changes resulting in an ipsilateral compression of cerebral peduncle on the tentorium- 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. Because hemispheric lesions typically cause contralateral weakness, this ipsilateral hemiparesis can be a false localizing sign that would suggest to the examiner that the patient has a lesion in the opposite, unaffected hemisphere.
Aqueductal compression- hydrocephalus
Intermittent compression of posterior cerebral artery- hemorrhagic infarct
to the territory supplied (Primary visual cortex)
Duret hemorrhage- tearing of perforating vessels from basilar artery
The posterior cerebral artery may also be compressed, resulting in ischemic injury to the territory supplied by that vessel, including the primary visual cortex.
o Progression of transtentorial herniation is often accompanied by
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 tearing of penetrating veins and arteries supplying the
upper brain stem. The presence of Duret hemorrhages implies a
grim prognosis
Uncal herniation
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Duret Hemorrhage involving brainstem at the junction of the pons and midbrain
2. TONSILLAR HERNIATION
Cerebellar tonsils herniated
Occipital bone surrounding foramen magnum-rigid strcture
Compression of cardiac and respiratory centers of medulla oblongata
Displacement of cerebellar tonsils through the foramen magnum
3. SUBFALCINE (CINGULATE) HERNIATION
Cingulate gyrus herniates under the falx cerebri (rigid structure)
Unilateral or asymmetric expansion of cerebral hemisphere
Compression of anterior cerebral artery- infarction
MALFORMATION AND DEVELOPMENTAL DISEASES
CNS MALFORMATIONS
Neural tube
- Anencephaly, encepahlocele, spina bifida
Forebrain
- Polymicrogyria, holoprocencephaly, agenesis of corpus callosum
Posterior fossa (infratentorial)
- Arnold Chiari (infratentorial herniation), Dandy- walker (cerebellar cyst)
Syringomyelia/ hydromyelia
Common CNS Malformations
Failure of neural tube to close or reopening. Encephalocele is a
diverticulum of malformed CNS extending through a defect in the
cranium. NTD most common CNS malformations. Spina bifida /
Spinal dysraphisms maybe an asymptomatic bony defect (spina bifida
occulta) or a severe malformation with a flattened disorganized
segment of spinal cord associated with meningeal outpouching in the
vertebral column. (Meningocele / Meningomyelocele)
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Failure of the prosencephalon to develop, and separate, often leads to Cyclops.
A. Spina bifida occulta
- Vertebral defect - Normal cord and meninges - Skin dimple with lipoma, tuft of hair, or sinus
B. Meningocele
- Vertebral defect - Herniation of meingeal sac through defect - Cystic CSF-filled mass covered by skin - Cord normal minimal neurologic deficit
C. Meningomyelocele - Vertebral defect - Herniation of cord and meningeal sac through defect- major
neurologic defect D. Spina bifida aperta
- Complete failure of fusion of neural plate - Skin and vertebral defect, base of which is undeveloped neural
plate major neurologic deficit
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Anencephaly malformation of the anterior end of the neural tube with absence of brain and calvarium.
Note the neural canal extends to the outside of the body. AFP, the same antigen found in hepatomas, is a good screening test for this. Neural tube defect is multifactorial both genetic and environmental factors are involved. Concordance rate is high in monozygotic twins and subsequent pregnancies.
90% of cases associated with Arnold-chiari type 2, remaining cases
posttraumatic and intraspinal tumors. Formation of a fluid filled
cleftlike cavity in the inner portion of the cord syringomyliea or into
the brainstem syringobulbia.
Loss of pain and temperature sensation in the upper extremities
Second of third decade of life
Hydromyelia central canal is simply dilated
(Right Pic) Absent corpus callosum
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Posterior fossa anomalies (arnold chiari)
2 types
1. Type 1 common, mostly asymptomatic
- Downward displacement cerebellar tonsils
2. Type 2 most often symptomatic, elongation and flattening of the
cerebellum and medulla with protrusion down a large conical foramen
magnum, compression of 4th ventricle, obstructive hydrocephalus; associated
with lumbar meningomyelocele and syringomyelia
Arnold Chiari Type 1 Arnold chiari II
Arnold Chiari Type 1: white outline shows ACM1 cerebellar tonsils extending through foramen magnum. Another figure shows Arnold Chiari type 2.
Arnold Chiari Type 2: most often symptomatic, elongation and flattening of the
cerebellum and medulla with protrusion down a large conical foramen magnum,
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compression of 4th
ventricle, obstructive hydrocephalus; assoc with lumbar
meningomyelocele and syringomyelia
signs/symptoms of ACM:
- Visual disturbances
- Slurred speech
- Wobbly walk
- Shaky hand
- Headache in the back of the head or neck which may be aggravated by
coughing, sneezing, or bending
- Numbness, tingling or weakness in the arm or hand
- Dyphagia
Dandy- walker (cerebellar cyst)
A Dandy-Walker malformation occurs when there is enlargement of the
posterior fossa with absent or rudimentary formation of the cerebellum,
which is replaced instead by a large midline cystic region representing the
expanded 4th ventricle
PERINATAL BRAIN INJURY Cerebral palsy
Prematurity
Intraparenchymal hemorrhage between the thalamus and caudate
nucleus
Periventricular leukomalacia- infarcts in the supratentorial white
matter
Multicystic encephalopathy- extensive ischemic damage involving both
gray and white matter
Nonprogressive neurologic motor deficit characterized by combinations
of spasticity,dystonia, ataxia/athetosis, and paresis
Important cause of childhood neurologic disability.
CNS TRAUMA Trauma to the brain and spinal cord is a significant cause of death and
disability
Severity and site of injury affect the outcome:
- Injury of several cubic centimeters of brain parenchyma may be
clinically silent (if in the frontal lobe)
- Severely disabling (spinal cord)
- Fatal (involving the brainstem)
Magnitude and distribution of traumatic brain lesions depend on:
The shape of the object causiong the trauma
Force of impact
Whether the head is in motion at the time of injury
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Physical forces associated with head injury may result in skull fractures, parenchymal injury and vascular injury.
SKULL FRACTURES: Displaced skull fracture
- Fracture in which bone is displaced into the cranial cavity by a distance
greater than thickness of the bone
Diastatic fractures
- Fractures that cross sutures
Basal Skull fractures
- Follows impact to the occiput or sides of the head
- Orbital or mastoid hematomas
- Symptoms referable to lower cranial nerves or cervicomedullary region
The kinetic energy that causes a fracture is dissipated at a fused suture. Fractures lines of subsequent injuries do not extend across fracture lines of prior injury.
TRAUMATIC PARENCHYMAL INJURIES: Coup injury
Contrecoup
Both coup and contrecoup lesions are contusions
A contusion is caused by a rapid tissue displacement,disruption of vascular
channels, and subsequent hemorrhage, tissue injury, and edema.
Crests of gyri are most susceptible
Most common locations where contusions occur:
- Frontal lobes along the orbital ridges
- Temporal lobes
When there is impact of an object with the head, injury may occur form
collision of the brain with the skull at the site of impact )a coup injury) or on
the opppsite side (contrecoup). Both coup and contrecoup lesions are
contusions, with comparable gross and microscopic appearances. Since they
are the points of impact, crests of gyri are most susceptible, whereas cerebral
cortex along the sulci is less vulnerable. The most common locations where
contusions occur correspond to the most frequent sites of direct impact and
to regions of the brain that overlie a rough and irregular inner skull surface,
such as
*Coup and Contrecoup developed when head is mobile at time of impact.
- Acute: wedge shape hemorrhage
- Subacute: necrosis and liquefaction of brain
- Remote: depressed area of cortex with yellow discoloration plaque jaunee
Contusions are less frequent over the occipital lobes, brainstem and cerebellum
Fracture contusions
- Contusions adjacent a skull fracture
Laceration
- Penetration of the brain, either by a projectile such as a bullet or a skull
fragment from a fracture,
- Tissue tearing, vascular disruption, hemorrhage and injury along a
linear path
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Figure : (A) Multiple contusions involving the inferior surfaces of the frontal lobes,anterior temporal lobes, and cerebellum. (B) Acute contusions are present in both temporal lobes, with areas of the hemorrhage and tissue disruption (arrows). (C) Remote contusions are present on the inferior frontal surface of this brain with a yellow color (associated with the term plaque jaune) (D)Multiple contusions involving the inferior surfaces of frontal lobes, anterior temporal lobes, and cerebellum(E).Acute contusions are present in both temporal lobes, with areas of hemorrhage and tissue disruption (arrows). (F) Remote contusions are present on the inferior frontal surface of this brain, with a yellow color (associated with the term plaque jaune).
(UpperR )The characteristic location of the hemorrhage in this brain is consistent with a fall backwards resulting in a contracoup injury to the inferior frontal and temporal lobes. This has resulted in extensive contusions and subarachnoid hemorrhage. Fall when awake occipital portion is the impact Fall unconscious frontal impact
Old hemorrhage
The orange brown, scalloped appearance of these lesions is consistent with old contusions. The resolution left behind hemosiderin from the hemorrhage that produces the orange brown staining.
PARENCHYMAL INJURIES Concussion:
Reversible altered consciousness from head injury in the absence of
contusion
Characteristic transient neurologic dysfunction:
- Loss of consciousness
- Temporary respiratory arrest
- Loss of reflexes
- Although neurologic recovery is complete, amnesia for the event
persists
- Pathogenesis of the sudden disruption of nervous activity is unknown
Diffuse axonal injury:
Injury to the white matter due to acceleration/ deceleration
Damage to axons at nodes of ranvier with impairment of axoplasmic flow
Diffuse but predilection for :
- Corpus callosum,periventricular white matter and hippocampus
- Cerebral and cerbellar peduncles
Coma after trauma without evidence of direct parenchymal injuties
Poor prognosis, related to duration of coma
Widespread, often asymmetrical axonal swellings that appear within hours
of injury
Increased numbers of microglia in related areas of cerebral cortex
Degeneration of involved fiber tracts
TRAUMATIC VASCULAR INJURY: Vascular injury results from direct trauma and disruption of the vessel wall,
leading to hemorrhage
Depending on which vessels rupture, hemorrhage may occur in any of
several compartments (sometimes in combination):
- Epidural
- Subdural
- Subarachnoid
- Intraparenchymal
Subarachnoid and intraparenchymal hemorrhages often occur at sites of
contusions and lacerations
Vascular injury results from direct trauma and disruption of the vessel wall,
leading to hemorrhage. Depending on which vessels rupture, hemorrhage may
occur in any of several compartments (sometimes in combination); epidural,
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subdural, subarachnoid, and intraparenchymal. Subarachnoid and
intraparenchymal hemorrhages most often occur at sites of contusions and
lacerations.
The dura is normally tightly applied to the inside of the skull, fused with the
periosteum. Vessels that run in the dura, most importantly the middle meningeal
artery, are vulnerable to injury, particularly with skull fractures. Once a vessel has
been torn, the accumulation of blood under arterial pressure can cause separation of
the dura from the inner surface of the skull. The expanding hematoma has a smooth
inner contour and compresses the brain surface.
The rapid movement of the brain that occurs in trauma can tear the bridging veins
that extend from the cerebral hemispheres through the subarachnoid and subdural
space to empty into dural spaces. These vessels are particularly prone in tearing, and
their disruption leads to bleeding into the subdural space. In elderly patients with
brain atrophy and infants are also susceptible to subdural hematomas.
(Left Pic) The dura has been reflected above to reveal the bridging veins that extend
across to the superior aspect of the cerebral hemispheres. These can be torn with
trauma, particularly if there is significant cerebral atrophy that exposes these veins
even more.
A blood clot is seen over the external surface of the dura. Thus, there is an epidural
hematoma. Such a location for hemorrhage is virtually always the result of trauma
that causes a tear in the middle meningeal artery.
epidural hematoma
Clinically, patients can be lucid for several hours between the moment of trauma and the development of neurologic signs. An epidural hematoma may expand rapidly and is a neurosurgical emergency requiring prompt drainage. Epidural hematoma covering a portion of the dura. Also present are multiple small contusions in the temporal lobe. Epidural Hematoma
- trauma usually severe ,associated with concussion and skull fracture (temporal
region)
- source: usually middle meningeal artery
- Course: acute
Subdural Hematoma
- Trauma usually mild
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- Source: usually bridging veins
- Course: slow (days to months)
Clinical features:
- Manifest within 48 hours of injury
- Most common over the lateral aspects of the cerebral hemispheres
- Bilateral in about 10% of cases
- Neurologic signs attributable to the pressure exerted on the adjacent
brain
- Nonlocalizing signs such as headache and confusion
- Multiple episodes of repeat bleeding (chronic subdural hematoma).
Presumable from the thin-walled vessels of the granulation tissue.
- Risk of repeat bleeding is greatest in the first few months after the
initial hemorrhage
Vebous bleeding is self-limited; breakdown and organization of the
hematoma take place over time. This usually occurs in the following
sequence:
- Lysis of the clot (about 1 week)
- Growth of fibroblasts from the dural surface into the hematoma (2
weeks)
- Early development of hyalinized connective tissue (1-3 months)
(R) The dura has been reflected back (with a small portion visible at the lower right) to reveal a subdural hematoma. Such a blood clot is usually the result of trauma with tearing of the bridging veins.
Subdural hematoma. Large organizing subdural hematoma attached to the dura.
Cross section of the brain showing compression of the hemisphere underlying the
subdural hematoma
(L) On macroscopic examination the acute subdural hematoma appears as a collection of freshly clotted blood apposed along the contour of the brain surface, without extension into the depths of sulci. The underlying brain is flattened, and the subarachnoid space is often clear. Typically, venous bleeding is self limited; breakdown and organization of the hematoma take place over time.
A. Large organizing subdural hematoma attached to the dura B. Coronal section of the brain showing compression of the hemisphere
underlying the subdural hematoma shown in A.
First pic: Child abuse. Subcutaneous hemorrhage In the retroauricular region Second pic: child abuse. Hemorrhage in the retina
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Child Abuse. Dura mater with chronic subdural hematoma showing fibrous
thickening and recent hemorrhages.
Child Abuse. Optic nerve sheath hemorrhage. There are hematomas in the
retrobulbar optic nerve sheaths of bilateral eyes in a case of shaking baby syndrome.
SEQUELAE OF BRAIN TRAUMA Post traumatic hydrocephalus
- Largely due to obstruction of CSF resorption from hemorrhage into the
subarachnoid spaces.
Post-traumatic dementia and the punch-drunk syndrome (dementia
pugilistica)
- Follow repeated head trauma during a protracted period; the
neuropathologic findings include hydrocephalus, thinning of the corpus
callosum, diffuse axonal injury, neurofibrillary tangles (mainly in the
medial temporal areas), and diffuse amyloid beta (AB)-positive plaques
Post-traumatic epilepsy, tumors (meningioma), infectious disease, and
psychiatric disorders.
A broad range of neurologic syndromes may become manifest months or years after trauma or any cause.
SPINAL CORD TRAUMA Injuries are usually traumatic due to vertebral displacement
Symptomatology depend on interruption of ascending and descending
tracts
Thoracic segments or below: paraplegia
Cervical segments: tetraplegia
Lesions above C4: paralysis of diaphragm
INTRACRANIAL HEMORRHAGE Primary Brain Parenchymal Hemorrhage
Spontaneous (nontraumatic) intraparenchymal hemorrhages- most
commonly in mid to late adult life
Peak incidence at about 60 years of age
Most are caused by rupture of small intraparenchymal vessel
Hypertension is the most common underlying cause
Brain hemorrhage accounts for roughly 15% of deaths among individuals
with chronic hypertyension
Chronic hypertension is associated with development of minute aneurysms
termed Charcot- Bouchard microaneurysm which may rupture
Hypertensive intraparenchymal hemorrhages typically occur in the basal
ganglia, thalamus, pons, cerebellum.
Intracerebral Hemorrhage
Clinical Features:
- May affect large portions of the brain and extends into the ventricular system
- Can affect small regions and be clinically silent
- Gradual resolution of the hematoma with considerable clinical improvement
- Location and size of the bleed will determine the clinical manifestations
- Acute hemorrhages
Over weeks or months there is a gradual resolution of the hematoma, sometimes with considerable clinical improvement. Again, the location and size of the bleed will determine the clinical manifestations.
- Old hemorrhages show an area of cavitary destruction of brain with a rim of
brownish discoloration
- On microscopic examination, the early lesion consists of:
Central core of clotted blood surrounded by a rim of brain tissue
Anoxic neuronal and glial changes
Edema
- Later lesions:
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Edema resolves
Pigment and lipid- laden macrophages appear
Proliferation of reactive astrocytes visible at the periphery of the
lesion
Acute hemorrhages are characterized by extravasation of blood with compression of
the adjacent parenchyma. Old hemorrhages show an area of cavitary destruction of
brain with a rim of brownish discoloration. On microscopic examination, the early
lesion consists of a central core of clotted blood surrounded by a rim of brain tissue
showing anoxic neuronal and glial changes as well as edema. Eventually the edema
resolves, pigment and lipid laden macrophages appear, and proliferation of reactive
astrocytes become visible at the periphery of the lesion. The cellular events then
follow the same time course observed after cerebral infarctions.
Subarachnoid Hemorrhage
Rupture of large intracerebral arteries which are the primary branches of
the anatomical circle (of Willis)
Congenital (berry aneurysm)
Atherosclerotic (atherosclerostic aneurysms, or direct wall rupture)
Subarachnoid Hemorrhage and Saccular aneurysms
Most frequent cause of subarachnoid hemorrhage is rupture of saccular
(berry) aneurysm
Rupture can occur at any time
Clinical features:
- In about 1/3 of cases associated with acute increases in intracranial
pressure
- Classically described as the worst headache Ive ever had
- Between 25% and 50% of individuals die with the first rupture
- Those who survive typically improve and recover consciousness in
minutes
- Recurring bleeding is common in survivors and prognosis worsens with each
episode of bleeding
Hemorrhage into the subarachnoid space may also result from vascular malformation, trauma (in which case it is usually associated with other sogns of the injury), rupture of an intracerebral hemorrhage into the ventricular system, hematologic disturbances, and tumors. Rupture can occur at any time, but in about one third of cases it is associated with acute increases in intracranial pressure, such as with strianing at stool or sexual orgasm. Blood under arterial pressure is forced into the subarachnoid space, and individuals are stricken with sudden, excruciating headache (classicall described as the worst headache ive ever had) and rapidly lose consciousness. Between 25% and 50% of individuals die with the first rupture, although those who survive typically improve and recover consiousness in minutes. Recurring bleeding is common in survivors; it is not possible to predict which individuals will have recurrences of bleeding. The prgnosis worsens with each episode of bleeding.
(R) Common sites (L) Classic berry aneurysm
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Circle of Willis
(L) The white arrow on the black card marks the site of a ruptured berry aneurysm in the circle of willis. The blood irritates the arteries to produce vasospasm and promote cerebral anoxia.
The adventitia covering the sac is continous with that of the parent artery. Rupture usually occurs at the apex of the sac with extravasation of blood into the subaracnoid
space, the substance of the brain, or both. A. View of the base of the brain,dissected to show the circle of willis with an
aneurysm of the anterior cerebral artery(arrow). B. dissected circle of willis to show
large aneurysm. C. section through a saccular aneurysm showing the hyalinized
fibrous vessel wall.
VASCULAR MALFORMATIONS
Classified into four principal types based on the nature of the abnormal
vessels:
1. arteriovenous malformations (AVM), the most common
2. cavernous angiomas
3. capillary telangiectasias
4. Venous angiomas
Affect males twice as frequently as females
Most often recognized clinically between the ages 10 and 30 years
Can present as seizure disorder
Intracerebral hemorrhage
Subarachnoid hemorrhage
The risk of bleeding makes AVM the most dangerous type of vascular
malformations
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(L) Another cause for hemorrhage, particularly in persons aged 10-30, is a vascular malformation. Seen here is a mass of irregular, tortuous vessels over the left posterior parietal region.
(R) AVMs involve vessels in the subarachnoid space extending into brain parenchyma or they may occur exlusively within the brain. In macroscopic appearance, they resemble a tangled network of wormlike vascular channels.
Microscopically, they are enlarged blood vessels separated by gliotic tissue, often with evidence of prior hemorrhage. Some vessels can be recognized as arteries with duplicated and fragmented internal elastic lamina, while others show marked thickening or partial replacement of the media by hyalinized connective tissues.
CEREBROVASCULAR DISEASES
Receives 15% of the resting cardiac output and 20% of the total body oxygen
consumption
May be deprived of the oxygen by several mechanisms of hypoxia and ischemia
Factors that determine injury extent:
o Presence of collateral circulation
o Duration of ischemia
o Magnitude and rapidity of reduction to flow
Third leading cause of death (after heart disease and cancer)
Three major categories
o Thrombosis
o Embolism
o Haemorrhage
Global cerebral ischemia
Focal Cerebral ischemia
Hypertensive cerebrovascular disease
Intracranial haemorrhage
HYPOXIA, ISCHEMIA and INFARCTION
A. GLOBAL CEREBRAL ISCHEMIA
- Generalized reduction of cerebral perfusion
- Cardiac arrest, shock, severe hypotension
- In mild state transient post-ischemic confusional state
- In severe state widespread neuronal death occurs brain death/respirator brain
- Penumbra (area at risk)
- Borderzone (watershed) infarcts
- Brain is swollen, gyri are widened, and sulsi narrowed
- Cut surface shows poor demarcation between gray and white matter
- Microscopic changes:
Early changes (12-24 after insult)
o Red neurons
o Infiltration by neutrophils
Subacute changes
o Necrosis of tissue
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o Influx of macrophages
o Vascular proliferation
o Reactive gliosis
Repair (2 weeks)
o Removal of necrotic tissue
o Loss of normally organized CNS structure
o Pseudolaminar necrosis
***Ischemic/hypoxic encephalopathy
-most susceptible to are the pyramidal cells in CA1 of the hippocampus, purkinje cells
of the cerebellum and cortical pyramidal neurons
B. FOCAL CEREBRAL ISCHEMIA
- Collateral flow
Circle of Willis
Distal branches of the anterior, middle, and posterior cerebral arteries
through cortical leptomeningeal anastomoses (surface of the brain)
No collateral flow for the deep penetrating vessels supplying structures as the
thalamus, basal ganglia and deep white matter
***infarction from obstruction of local blood supply
- Thrombotic Occlusions Atherosclerosis
Common sites
o Carotid bifurcation
o Origin of middle cerebral artery
o End of the basilar artery
- Embolism
Cardiac mural thrombi
Thromboemboli arising in arteries (carotid arteries
Other sources of emboli
Territory of distribution of MCA most frequently affected
Emboli tend to lodge on where blood vessels branch or in pre-existing luminal
stenosis
C. INFARCTS
- Two broad categories:
Hemorrhagic (red) infarct
o Multiple/confluent petechial hemorrhages
o Associated with Embolic Events
o Presumed to be secondary to repurfusion of damage vessels and tissues
Non-hemorrhagic infarct associated with thrombosis
- Gross:
Frist 6 hours little can be observed
48 hours tissue becomes pale, soft, swollen, and corticomedullary junction
becomes indistinct
2-10 days brain becomes gelatinous and friable with more distinct boundary
10 days to 3 weeks tissue liquefies, fluid filled cavity lined by dark gray tissue
- Microscopic:
After 1st
12 hours ischemic neuronal change, loss of demarcation of white
and gray matter
Up to 48 hours neutrophilic emigration progressively increases and then
falls off, phagocytes are evident
1 week reactive astrocytes canbe seen
2-3 weeks phagocytosis ensues
HYPERTENSIVE CEREBROVASCULAR DISEASE
- Effects of hypertension on the brain:
Include massive hypertensive intracerebral haemorrhage
Lacunar infarcts
Slit hemorrhages
Hypertensive encephalopathy
- Lacunar Infarcts
Lake-like spaces,
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***these small cavitary infarcts are just a few mm wide (
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***the neurons are the most sensitive cells to anoxic
injury. Seen here are red neurons which are dying as
a result of hypoxia. One of the most sensitive areas
in the brain to hypoxic injury is the hypothalamus
COMMON NEUROVASCULAR SYNDROMES
- Anterior cerebral artery
Weakness and sensory loss in contralateral
leg
Transient expressive aphasia
Abulia
- Middle cerebral artery
Contralateral hemiplegia
Contralateral sensory loss
Aphasia if dominant hemisphere affected
- Posterior cerebral artery
Contralateral hemianopia or total cortical blindness of bilateral
Alexia with agraphia
Thalamic syndrome
CNS TUMORS - Symptoms: ***usually very slow and subtle onset
Headache
Vomiting
mental changes
motor problems
Seizures
increased intracranial pressure
any localizing CNS abnormality
History
Physical
Neurologic exam
LP (including cytology)
CT
MRI
Brain angiography
Biopsy
Benign? Malignant? primary vs met? location? age? X-ray density? MRI
signals? Calcifications? Vascularity? Necrosis? Liquefaction? Edema?
Compression of neighbors?
- GLIOSIS vs GLIOMA
Age? White vs gray matter? Gross texture? Vascularity? Mitoses? (N/C,
pleomorphism, hyperchromasia) calcifications? Cysts? Satellitosis?
Delineation?
***differential between gliosis and a well differentiated glioma can be
gruellingly diffiuclt
- GLIOMAS (do not metastasize out of CNS)
Astrocytes (I, II, III, IV)
Oligodendroglioma
Ependymoma
- NEURONAL (Gangliogliomas)
- POORLY DIFFERENTIATED (Medulloblastoma)
- MENINGIOMAS
- LYMPHOMAS
- METASTATIC
Common intracranial neoplasms classifies according to
location and age
Location Children Adults
Supratentorial
Cerebral
hemisphere
30%
Rare
70%
Glial neoplasms
Meningiomas
metastasis
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Suprasellar Craniopharyngioma
Juvenile pilocytic
astrocytoma
Pituitary adenoma
Craniopharyngiom
a
Glial neoplasms
Pineal Pineoblastoma
Germ cell tumor
(teratoma)
Pineocytoma
Germ cell tumor
(germonima)
Infratentorial
(posterior
fossa)
Midline
70%
Medulloblastoma
Ependymoma
30%
Brain stem glioma
Cerebellar
hemisphere
Juvenile pilocytic
astrocytoma
Metastases
Hemangioblastom
a
Cerebellopontin
e angle
Epidermoid cyst Schwannoma
(acoustic
neuroma)
Meningioma
CLASSIFICATION OF CNS TUMORS
CYTOLOGIC ORIGIN OF CNS TUMORS
- Neuro-ectodermal most important are the Gliomas
- Mesenchymal most frequent ones are the Meningiomas
- Ectopic tissues from tissues displaced during embryogenesis (ex: Dermoid cyst)
- Retained embryonal structures- various cysts Paraphyseal cyst
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- Metastases lung, breast, melanoma etc in 50% of cases
I. NEURO-ECTO DERMAL TUMORS
- Glial cells:
Astrocytes (A) Astrocytoma
Oligodendroglial cells Oligodendroglioma
Ependymal cells Ependymoma
- Neurons Gangliocytoma
Astrocytomas
- Account for ~80% of primary ICTS in adults
- MC in the cerebral hemispheres
- MC Syndromes: headaches, seizures, focal neurologic defeicits (usually in the
anterior or middle)
- Low-grade Astrocytomas:
o Gross: Poorly defined gray-white infiltrative tumors
o Histology: hypercellularity; astrocytic nuclei of mild degree of atypia and
astrocytic process fibrillary background fingers of astrocytes
o Pilocytic Astrocytomas:
o MC in the cerebellum of children and young adults; and less commonly in
the optic nerve, hypothalamic region or cerebral hemispheres
o Morphology:
Cystic, with a tumor nodule in the wall of the cyst
Composed of bipolar astrocytes, with long hair-like processes, Rosenthal
fibers and Micro-cysts + calcification = good prognosis
o Grow very slowly (some patients have survived for >40 yrs after incomplete
resection) and have an Excellent Prognosis
o DD; not tot confused with low-grade Fibrillary Astrocytoma
***upto grade 2: surgery is enough
Beyond grade 2: radiotherapy must be added
Grade I Tumor: Pilocytic Astrocytoma
***optic glioma
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***NB fibrillary background
Rosenthal Fibers
Grade II Astrocytoma
- Poorly defined, gray infiltrative tumor that expands and distorts the invaded brain
- Cut surface is either firm, soft, and gelatinous
***hypercellularity + nuclear atypia
- Mild to moderate increase in glial cellularity, variable nuclear
pleomorphism, GFAP positive astrocytic processes. Indistinct transition
between neoplastic and normal tissue
***Glioma intermediate grade
Grade III Astrocytoma
***Poorly defined, gray infiltrative tumor that expands and distords the invaded
brain; Cut surface is either frim, soft and gelatinous
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- More densely cellular and greater nuclear pleomorphism
- Mitotic figures are often observed
- NO NECROSIS
***Inc cellularity + nucleat atypia + mitotic figures
Grade IV ASTROCYTOMA GBM
Variation in gross appearance of the tumor
GBM: necrosis/pseudo-palisade
**pseudopallisading central necrosis with perpendicular cells
Glioma, high grade: Necrosis is needed for the diagnosis of high grade glioma
Glioblastoma multiforme
Hallmark of GBM: palisading and necrosis
GBM: Pleomorphic cytology
Gr. IV Astro= GBM
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Genetic pathways operative in the evolution of primary and secondary
glioblasotoma.
**secondary younger patient
Primary older patient
***Central necrosis is a sign of rapid growth. It outgrowths its blood supply, and
therefore liquefies centrally, like an abscess.
Non-Astrocytic Gliomas
**tumor of glial cells that look like oligodendrocytes
- Sheets of regular cells with spherical nuclei containing finely granular chromitin
- Delicate network of capillaries
- Calcification in 90% of tumors
- Perineural satellitosis
- Mitotic activity and proliferation index is low
- Characterized by increased cell density, increased mitotic activity and necrosis
- Show pattern indistinguishable from Glioblastoma
- WHO Grade III/IV
Oligodendrioglioma
- 5-15% of gliomas
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- 4th
and 5th
deades
- Found mostly in the cerebral hemispheres with a predilection for white matter
- Considered as WHO grade II/IV lesions
- Grossly: Well-circumscribed neoplasm often with speckled calcification
- Clinical features:
Better prognosis than those with astrocytomas
Average survival of 5-20 years after intervention
Recurrence is common
- Molecular genetics
Loss of heterozygosity for chromosome 1p and 19q most common
Additional alterations seen in Anaplastic Oligodendrioglioma include loss of
9p, loss of 10q, and mutation in CDKN2A
EGFR gene amplication not seen in these tumor
**Normal ependymal on the left. Would a choroid plexus tumor be a type of
ependymoma? Yes
Ependymoma
- Arise next to the ependymal-lined ventricular system, including the soft-obliterated
central canal of the spinal cord
- First two decades typically occur near the 4th
ventricle and constitute 5-10% of
primary brain tumors in this age group
- Grossly:
Well-circumscribed solid masses extending from the floor of the ventricle
The proximity of the tumor to the pontine and medullary nuclei makes
complete extirpation impossible
While complete removal is possible for intraspinal tumors
- Microscopically:
Regular round to oval nuclei and abundant granular chromatin
Dense fibrillary background
Cells may form glandlike round or elongated structures that resemble the
embryonic ependymal canal
Perivascular pseudorosettes
- Myxopapillary Ependymomas
Specific type of ependymoma occurring in the filum terminale and presents as
cauda equine tumor in young adults
Papillary elements in a myxoid background admixed with ependymoma-like
cells
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Myxoid areas contain neural and acidic mucopolysaccharides
- Clinical features:
Often manifest with hydrocephalus
CSF dessimination is common
Posterior fossa lesions have worst outcomes (5yr survival rate of 50%)
NF2 gene on chromosome 22 often seen in spinal ependymomas
Supratentorial lesions more likely show alterations in chromosome 9
Other Tumors
-SUBEPENDYMOMAS
Usually an incidental or autopsy findings
Solid, sometimes calcified, slow growing nodules attached to the ventricular
lining and protruding into the ventricle
May case hydrocephalus if sufficiently large
Microscopically are clumps of ependymal appearing nuclei scated in a dense
fine glial fibrillar background.
- CHOROID PLEXUS PAPILLOMA
Most common in children in the lateral ventricles, in adults seen in the fourth
ventricle
Consists of markedly papillary outgrowths that recapitulate choroid plexus
Cause hydrocephalus either due to obstruction or overproduction of CSF
Malignant counterpart Choroid plexus carcinoma
- COLLOID CYST OF THE THIRD VENTRICLE
Non-neoplastic lesion in young adults that is attached to the roof of the third
ventricle
Can obstruct foramen of Monro and cause noncommunicating hydrocephalus
Thin fibrous capsule that contains gelatinous proteinaceous material
NEURONAL TUMORS
Gangliogliomas
Most common CNS tumor containing mature ganglion cells admixed with glial
neoplasm
Slow growing but can become frankly anaplastic
Often present as seizure disorder; surgical resection is effective
Dysembryoblastic Neuroepithelial Tumors
Low-grade tumor of childhood that presents as seizure disorder
Located typically in the superficial temporal lobe
Multiple discrete intracortical nodules of small round cells, arranged in
columns around central cores od processes in a myxoid background specific
glioneuronal element
Focal cortial dysplasia and low-grade astrocytoma sometimes seen
surrounding the nodules Complex
**well-differentiated floating neurons that dit in the pool of
mucopolysaccharide rich fluid of myxoid background
Central Neurocytoma
Low-gradeusually in the lateral or third ventricles
Characterized by evenly spaced round, uniform nuclei and islands of neuropil
POORLY DIFFERENTIATED NEOPLASMS
Medulloblastoma
Occurs predominantly in children and exclusively in the cerebellum
Located in the midline of cerebellum in children, but lateral in adults
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May occlude flow of CSF
Highly malignant
With total excision and irradiation (5yr-75%)
Dissemination through CFS is common, metastasize to the cauda equine (drop
metastases)
Often well-circumscribed, gray and friable
***sagital section of the brain shwoing medulloblastoma destroying the
superior midline cerebellum
Extremely cellular
Individual tumor ccells are small, with scant cytoplasm and hyperchromatic
nuclei that are frequently elongated or creascent shaped
High proliferation index
Express neuronal (neurosecretory) granules or Homer Wright rosettes and
glial phenotypes
Molecular genetics
o Most common genetic alteration is loss of material from 17p (poor
prognosis), with an abnormal chromosome derived from its long arm
(isochrome 17q)
o MYC amplification can be seen with aggressive tumors
o Other signalling pathways
Sonic-hedgehog-patched pathway
WNT signalling pathway
Notch signalling pathway
***any midline cerebellum tumor in a child is a medulloblastoma till proven
otherwise
Are medulloblastoma PNET tumors? YES!
So does that mean that will look like small cell carcinoma or Ewing or lymphoma or
any ther small round blue cell tumor? YES!
**quiz: Midline cerebellum tumor in a kid. What is it? Ans: Medulloblastoma, always,
unless proven otherwise.
Atypical Teratoid/ Rahbdoid Tumor
Highly malignant tumor of young children occurs in the posterior fossa
and supratentorial compartments in nearly equal proportions.
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Occur before age of 5 and live less than a year
Presence of rhabdoid cells is the defining characteristic of the lesion
Tend to be large with soft consistency and spread along the surface of
the brain
IHC: (+) EMA,CK,SMA,VIM;
(-) Desmin and Myoglobin
Molecular Genetics
Alteration in Chromosome 22 (90%)- Hallmark
Relevant gene is hSNF5/INI1
- encodes protein involved in chromatin remodeling
Functional deletions of the locus and loss of nuclear staining for INI1
protein seen in majority of the tumors
OTHER PARENCHYMAL TUMORS
Primary CNS Lymphoma
2% of extranodal lymphomas and 1% of intracranial tumors
Most common CNS neoplasm in immunosuppressed in AIDS /post transplant
In the setting of immunosuppression, tumor cells are latently infected with
EBV
Metastases outside CNS is rare
Most are B-cell origin
Frequently multiple and often involve deerp gray matter as well as white
matter and cortex
Periventricular spread is common
DLBCL- most common histologic group
Germ Cell Tumors
Occur along the midline (pineal and suprasellar regions)
Tumors of the young (90% first two decades)
metastasis of the gonadal germ cell tumor is not uncommon
AFP and -HCG can be used to aid in the diagnosis and track response to therapy
Pineal Parenchymal Tumors
Arised from specialized cells (pieocytes) that have the feature of Neuronal
Differentiation
Pineocytomas-well differentiates lesions; adults
Pineoblastomas- high grade lesions; children
Craniopharyngioma
Derived from the Rathkes pouch
Occurs mainly in childhood adjacent to the pituitary stalk
Compression and destruction of the pituitary, optic chiasm and third ventricle
Treatment is surgical with high recurrence rate
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Chordoma
Neoplasm derived from the notochordal remnants found in the base of the
skull and dorsal aspect of the vertebral bodies
Occurs commonly in the sacrococcygeal region, clivus from which it extends
to the posterior fossa and suprasellar region
MENINGIOMAS
occurs where dura is and arise from the meningothelial cells of arachnoid
may occur in the ventricular system and arise from stromal arachnoid cells of
the choroid plexus
very vascular
BENIGN, but (can be invasive)
Can invade the skull, etc.
Only invadr (displace) brain in areas adjacent to the dura, i.e., parasagittal,
falx, tentorium, venous sinuses
Small, firm, and well defined like a SUPERBALL
Often (usually?) have PSAMMOMA bodies
Usually rounded masses with well defines dural bases
May also grow en plaque (sheetlike fashion) and commonly associated with
hyperostotic reactive changes
Lesions range from firm to fibrous, gritty (psammoma)
No necrosis or extensive hemorrhage present
Positive for EMA and CEA
Common sites of involvement include:
Parasagittal aspect of the brain convexity
Dura over the lateral convexity
Wing of the sphenoid
Olfactory groove
Sella turcica
Foramen magnum
Uncommon in children
3:2 female predominance; 10:1 in spinal menigiomas
Often express progesterone receptors ad may grow rapidly in pregnancy
Histologic Patterns
WHO GRADE I/IV
Low risk of recurrence
Syncytial (meningothelial)
- whorled clusters of cells that sit in tight groups without visible cell
membranes
Fibroblastic
- with elongated cells and abundant collagen deposition between them
Transitional
- share features of the syncytial and fibroblastic types
Psammomatous
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- with psammoma bodies, apparently formed from calcification of the
syncytial nests of meningothelial cells
Secretory
- PAS- Positive intracytoplasmic droplets and intracellular lumens
Microcystic
- with a loose, spongy appearance.
Atypical meningiomas (WHO GRADE II/IV)
- Higher risk of recurrence/ more aggressive local growth
- Distinguished by either mitotic index of four or more per 10 hpf or at least three
atypical features (increased cellularity, small cells with high N/C ratio, rpominen
growth or necrosis)
Clear cell
Chordoid
Anaplastic (malignant) Meningioma (WHO GRADE III/IV)
- Highly aggressive tumor with high propensity to recur
Papillary (pleomorphic cells arranged around fibrovascular cores)
Rhabdoid (sheets of tumor cellswith hyaline eosinophilic cytoplasm containing
intermediate filaments)
Molecular Genetics
Loss of Chromosome 22- most common (region of 22q12 that harbors NF2 gene)
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METASTATIC CNS TUMORS
LUNG
BREAST
MELANOMA
KIDNEY
GI
CHORIOCARCINOMA
Meningial Carcimatosis with tumor nodules studding the surface of the brain,
spinl cord and intradural nerve roots is associated particularly with lung and
breast CA
PARANEOPLASTIC SYNDROME
SMALL CELL, LUNG
LYMPHOMAS
BREAST CA
Purkinje cell degeneration
Encephalitis, Limbic System
Sensory Neuron Degeneration, DRG
Eye Movement Disorders
Subacute sensory neuropathy
Lambert- Eaton Myasthenic Syndrome
PERIPHERAL NERVE SHEATH TUMORS
Tumors arise from cells of the peripheral nerve, including schwann cells,
perineural cells and fibroblast
Can arise within the dura and along the peripheral course of nerves
Benign
- Schwannoma
- Neurofibroma
Malignant Peripheral nerve Sheet Tumor
Schwannoma
Clinical features:
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- Also called neurilemmoma
- Can occur at any age; typically adulthood
- Common sites of involvement are intracranial sites (cerebellopontine
angle) where they are attached to the 8th
nerve (Acoustic Neuroma)
- Slow growing; usually painless tumor
- Most often sporadic; less than 5% occur in patients with
neurofibromatosis type 2 (NF2)
Gross pathology
- Ovoid or fusiform mass, usually smaller than 5 cm
- Well-defined and typically encapsulated with pink to tan, firm cut surface
- Focal areas of cystic degeneration may be seen
Histopathology
- Well defined capsule consisting of epineurium
- Presence of compact hypercellular areas (Antoni A areas) and
hypocellular, myxoid aread (Antoni B areas)
- Nuclear palisading around fibrillary processes (Verocay bodies)
- Cells are spindled and contain elongated wavy nuclei with tapered ends
- Hyalinized vessels are characteristic
- Focal areas of hemorrhage, hemosiderin deposition, and xanthomatous
change
- Rarely have glandular structures or pure epitheloid morphology
Special Stains and Immunohistochemistry
- S-100 protein strongly positive
- Leu-7 (CD57,CD56 and GFAP positive
- Collagen IV: surround individual tumor cells
Other Technique of Diagnosis
- Electron microscopy: tumor cells contain electron dense basement
membrane material and characteristic Luse bodies (long- spaced
collagen)
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Neurofibroma
Clinical Feature
- Usually occur in the dermal or SQ tissues throughout the body
- People of any age can be affected, but seen most commonly in young
adults
- Lesions may be localized, diffuse, or plexiform, the latter two having a
strong association with NF1
NF1, von Recklinghausen disease
- Autosomal dominant, chromosome 17
- Positive family history in most cases
- Multiple neurofibromas at different areas of the body
- Caf-au-lait spots (hyperpigmented skin lesions)
- Lisch nodules (pigmented iris hemartomas)
Gross Pathology
- Well-defines fusiform lesion often in association with a nerve trunk
- Firm, gray-white cut surface
- Diffuse lesions show ill-defined, plaque-like thickening of the Sq tissues
- Plexiform lesions are multinodular conglomerate of lesions of likened to a
bag of worms
Histopathology
- Low to moderat cellular lesion composed of cells with wavy nuclei and
eiosinophilic cytoplasm interspersed with wisps of collagen
- Stroma may show small amounts of mucoid material or be myxoid and is
occasionally hyalinized
- Tumor is well circumscribed but usually not encapsulated
- Mild nuclear atypia is common and does not mean malignant
transformation
- May contain melanin pigment (pigmented neurofibroma) or show
epithelioid morphology (epithelioid neurofibroma)
Plexiform Neurofibroma
- Almost exclusively associates with NF1
- Irregularly expanded nerve bundles giving a multinodular appearance
- Tend to be hypocellular with a prominent myxoid matrix
- var able degrees of nuclear pleomorphism may be seen
- infrequent mitotic activity
Diffuse Neurofibroma
- Neoplastic cells expand the dermal and SQ tissues and envelop SQ and
adnexal structures
Special stains and Immunohistochemistry
- S-100 protein positive
Other techniques for Diagnosis
- Biallelic loss of NF1 tumor suppressor gene on chromosome 17q11.2 may be
demonstrated by molecular techniques
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Malignant Peripheral Nerve Sheath Tumor
Clinical Feature
- Typically presents as an enlarging mass arising in association with a major
nerve trunk, frequently on proximal extremities
- About 3% to 10% of patients with NF1 develop a malignant peripheral
nerve sheath tumor (MPNST)
- About 50% of cases are found in patients with NF1 often develops after
10 to 20 years
- Sporadic cases typically develop in adults with a male to female ratio of
1:1
- Cases associated with neurofibromatosis occur at a younger age and
show a 4:1 male to female ratio
Gross Pathology
- Arises as a fusiform, deep seated mass often within a major nerve
- Tumors are typically poorly defined and frequently infiltrate along
adjacent nerve or into adjacent soft tissue
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- Tan-white, fleshy cut surface with focal areas of hemorrhage and necrosis
Histopathology
- Cellular spindle cell tumor with fascicular growth pattern
- Alternating hypercellular and hypocellular zones of ten with areas of
myxoid stroma
- Nuclear palisading and whorled nodules of spindle cells may be seen
- Perivascular tumor cell condensation and growth along nerve twigs is
common
- Spindle cells show hyperchromatic wavy or buckled nuclei and show
minimal to marked pleomorphism
- High mitotic activity and necrosis is common
- Benign or malignant heterologous elements such as bone, cartilage and
skeletal muscle may be seen
Malignant triton tumor
- Presence of rhabdomyolblastic differentiation
MPNST
- Tumor showing areas of conventional MPNST admixed with nests of
round to polygonal epithelioid cells with round nuclei, prominent
nucleoli, and clear to eiosinophilic cytoplasm.
Special stains and Immunohistochemistry
- S-100 protein focally and weakly positive in most cases
- CD56 and CD57 variably positive
- Collagen IV positive around individual tumor cells
Other techniques for diagnosis:
Electron Microscopy
- Interdigitating cell processes, complete or partial external lamina, cell
junctions and pinocytotic vesicles
Cytogenic studies
- Numerous structural and numeral abnormalities, none of which are
diagnosic
Differential Diagnosis
- Cellular Schwannoma
- Leiomyosarcoma
- Fibrosarcoma
- Synovial Sarcoma
- Clear Cell Sarcoma
FAMILIAL TUMOR SYNDROMES
NF1
- Neurofibromas
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- Gliomas
NF2
- Schwannomas
- Meningiomas
Tuberous Sclerosis, i.e., CNS and Somatic Hemartomas
Von-Hippel-Lindau, CNS hemangioblastomas, chiefly cerebellar
Phakomatoses
NEUROCUTANEOUS SYNDROMES
AD
Hemartomas and Neoplasms
- Esp. involving the nervous system and skin
- Mutations in tumor suppressor gene
1. Neurofibromatosis Type 1 (NF1)
- Neurofibromas, Neurofibro-sarcomas
- Optic Neve Gliomas
- Pigmenes cutaneous macules (caf au lait spots)
- Pigmented nodules of iris (Lisch nodules)
2. Neurofibromatosis Type 2 (NF2)
- Bilateral Schwannomas of CN VIII
- Multiple Meningiomas
- Spinal Cord Ependymomas
3. Tuberous Sclerosis
- Hamartomas (tubers) in the cerebral cortex, SubEpendumal hamartomas
(candle drippings) -> Sub-Ependymal giant cell Astrocytomas
- Seizures and mental retardation
- Extra CNS findings:
Kidney (Angiomyolipoma), heart (Rhabdomyoma MCC in kids,
Mixomas in adults), skin (Angiofibroma)
4. Von Hippel-Lindau Disease
- Hemangioblastomas of the cerebellum, retina, brain stem and spinal cord
- Cysts of liver, kidney and pancreas
- incidence of RCC, may be bilateral
- 10% of Hemagioblastomas polycythemia
Cowden Syndrome
- Dysplastic ganglioglicytoma of the cerebellum (Lhermitte-Duclos Disease),
caused by mutations in PTEN resulting in increased activity of AKT and
mTOR pathways
Li-Fraumeni Syndrome
- Medulloblastomas, caused by mutation in p53
Turcot Syndrome
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- Medulloblastoma or glioblastoma, caused by mutations in APC or
mismatch repair genes
Gorlin Syndrome
- Medulloblastoma, caused by mutations in the PTCH gene resulting in up
regulation of sonic hedgehog signaling pathway.
CNS INFECTION Types of CNS INFECTION:
MENINGITIS
(inflammatory process of the leptomeninges and CSF within the
subarachnoid space, while meningoencephalitis cobines this with
inflammation of the brain parenchyma)
Infectious Meningitis
- Acute Pyogenic Meningitis (Bacterial)
- Aseptic Meningitis (Viral)
- Chronic Meningitis (TB, SPirochetal, Cryptococcal)
Chemical Meningitis (nonbacterial irritant)
CEREBRITIS/ABSCESS
ENCEPHALITIS/ENCEPALOMYELITIS/LEUKOENCEPHALITIS
Route of Entry
Hematogenous- most common
(either through arterial circulation or via retrograde venous spread through
anastomoses with veins of the face)
Direct Implantation- trauma, iatrogenic
(congenital defects, shunts, etc)
Local extension- mastoid, pharynx, tooth
Peripheral Nervous System- rabies &herpes zoster
ACUTE MENINGITIS Acute Pyogenic (Bacterial) Meningitis
Common causative organisms:
o Neonates: E. Coli and group B streptococci
o Adolescents / Adults: Neisseria Meningitidis
o Elderly: Streptococcus pneumoniae and Listeria Monocytogenes
o Other uncommon: Klebsiella / Anaerobic Organisms
Signs / Symptoms
o Headache
o Photophobia
o Irritability
o Clouding of consciousness
o Neck stiffness
CSF Findings
o High pressure
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o Cloudy / Purulent CSF (inc WBC)
o Inc Protein
o Markedly reduced glucose
Outcome
o Plebitis
o Focal Cerebritis
o Venous Thrombosis
o Hemorrhagic infarction
o Leptopmeningeal infarction
o Chronic adhesive arachnoiditis (Arachnoid fibrosis)
o Communicating hydrocephalus
o Cerebral infarcts
o Cranial nerve defects blindness, deafness
o Mental retardation, language defects, motor deficits, etc
o Death
Microscopic examination, neutrophils fill the subarachnoid space in severely affected
areas and are found predominantly around the leptomeningeal blood vessels in less
severe cases. In untreated meningitis, gram stain reveals varying numbers of the
causative organism, although they are frequently not demonstrable in treated cases.
In fulminant meningitis, the inflammatory cells infiltrate the walls of the
leptomeningeal veins and may extend into the substance of the brain (focal
cerebritis). Phlebitis may also lead to venous thrombosis and hemorrhagic infarction
of the underlying brain. Leptomeningeal fibrosis may follow pyogenic meningitis and
cause hydrocephalus. In some infections, particularly in pneumococcal meningitis,
large quantities of the capsular polysaccharide of the organism produce a
particularly gelatinous exudates that encourages arachnoid fibrosis called chronic
adhesive arachnoiditis.
SUPPURATIVE MENINGITIS PATHOLOGY
Acute Phase
o Pus in meninges, Virchow Robin spaces
o Cerebral Edema
Subacute / chronic phase
o Fibrin and mononuclear cells
o Vasculitis, thrombosis, infarct
o Fibrosis
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Acute Aseptic Meningitis
Absence of recognizable organisms
Maybe viral, bacteria or others (chemical)
Less fulminant
Lymphocytic pleocytosis (viral)
Pleocytosis with neutrophils in chemical / irritant
CSF Glucose normal
Protein conc moderately increased
Self limiting
ACUTE FOCAL SUPPURATIVE CNS INFECTIONS CEREBRAL ABSCESS
o Direct implantation
o Local extension (mastoiditis, sinusitis)
o Hematogenous (Cong. Heart Disease, bact. Endocarditis, tooth
extraction, chronic pulmonary sepsis)
o Staph, Strep gnonimmunosupresses
o Often fibrous capsule, liquid center
SUBDURAL EMPYEMA (IN SINUSITIS)
EXTRADURAL ABSCESS (IN OSTEOMYELITIS)
Brain Abscess
Suppurative necrosis of brain parenchyma
Sources: congenital heart diseases, valvular heart diseases, lung abscess,
bronchiectasis, dental abscesses, mastoiditis
Organisms: S. Aureus, S. Viridans, streptococci, anaerobes, Actinomyces,
Nocardia etc.
Abcesses are discrete lesions with cental liquefactive necrosis surrounded by
fibrosis and swelling
Exuberant granulation tissue with neovascularization around the necrosis that is
responsible for marked vasogenic edema. A collagenous capsule is produced by
fibroblasts derived from the walls of the blood vessels. Outside the fibrous
capsule is a zone of reactive gliosis with numerous gemistocytic astrocytes.
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Clinical Features
o Signs of increased ICP
o Focal Deficits
o Inc WBC, Protein ; Normal Glucose
o Herniation
o Rupture Ventriculitis, Meningitis
o Mx: Surgery and Antibiotics
Subdural Empyema
Bacterial or fungal infections of skull bones / air sinuses
Produce mass effect if large
Thrombophlebitis
Venous Occlusion and infarction
The underlying arachnoid and subarachnoid spaces are usually unaffected, but a
large subdural empyema may produce a mass effect. Further, a thrombophlebitis
may develop in the bridging veins that cross the subdural space, resulting in venous
occlusion and infarction of the brain. Symptoms include those referable to the source
of the infection. In addition, most patients are febrile, with headache and neck
stiffness, and, if untreated, may develop focal neurologic signs, lethargy, and coma.
The CSF profile is similar to that seen in brain abcesses.
Extradural Abscess
Commonly associated with osteomyelitis from adjacent forcus (sinusitis /
surgical procedure)
Spinal Epidural abscess may cause spinal cord compression
Tb Meningoencephalitis
M. Tuberculosis enters CNS by hematogenous route during primary
infection
Most common pattern is diffuse meningoencephalitis
Complications
o Obliterative endarteritis aterial occlusion and infarction
o Fibrous adhesive arachnoiditis
o Hydrocephalus
Maybe isolated or a part of systemic disease with involvement if the meninges and or
brain often together.
Tuberculosis
TUBERCULOMA space occupying lesion
o Cerebellum and pons most common sites
Potts disease
o TB of vertebral body
o Spinal cord compression from vertebral collapse
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Another manifestation of the disease is the developmnet of a single (left) (or
often multiple (right)). They are well circumscribed intraparenchymal mass
which may be associated with meningitis. A tuberculoma may be as large as
several centimeters in diameter, causing significant mass effect.
Microscopic examination, there are mixtures of lymphocytes, plasma cells, and
macrophages. Florid cases show well-formed granulomas, often with caseous
necrosis and giant cells.
HIV-positive individuals are also at risk for infection by M. avium-intracellulare,
usually in the setting of disseminated infection. These lesions typically contain
confluent sheets of macrophages filled with organisms, with little or no
associated granulomatous reaction.
Tuberculosis
Clinical Features
o Symptoms
Headache
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Malaise
Mental Cofusion
Vomiting
o CSF Findings
Moderate CSF pleocytosis
High Protein
Glucosel sl. Dec to normal
Neurosyphilis
Manifestation of the tertiary stage of Syphilis
Major Patterns
o Meningovascular Syphilis
o Paretic Neurosyphilis
o Tabes dorsalis
Seen in 10% of untreated cases
Meningovascular Syphilis
Chronic meningitis
Obliterative Endarteritis with perivascular inflammatory reaction
Cerebral Gummas
Chronic meningitis involving the base of the brain and more variably the cerebral
convexities and the spinal leptomeninges.
Paretic Neurosyphilis
Manifested as insidious but progressive mental deficits with mood
alterations, severe dementia (general paresis of the insane)
Microscopic findings:
o Loss of neurons
o Proliferation of microglia (rod cells)
o Gliosis
o Iron deposits
o Granular ependymitis
Invasion of the brain parenchyma by T. Pallidum
Inflammatory lesions are associated with parenchymal damage
Iron deposits are due to small bleeds from microcirculation
Granular ependymitis proliferation of subependymal glia
Hydrocephalus can also be a manifestation with damage to the ependymal lining
Tabes Dorsalis
Damage of the spirochetes to the sensory nerves in the dorsal roots
Clinical Manifestations:
o Impaired joint position sense
o Locomotor ataxia
o Loss of pain sensation
o Charcot joints (skin and joint damage)
o Lightning pains
o Absent DTR
Microscopic Findings:
o Loss of boyh axons and myelin in the dorsal roots
o Pallor and atrophy in the dorsal columns of the spinal cord
o Organisms not demonstrable
Neuroborreliosis (Lyme Disease)
Borrelia burgdorferi transmitted by Ixodes tick
Neurologic Symptoms: Aseptic Meningitis, facialnerve palsies,
polyneuropathies, encephalopathy
Microscopic findings: Focal proliferation of microglial cells with scattered
ectracellular organisms
Viral Meningoencephalitis
Arthropod Borne Viral Encephalitis
HSV Type 1 Encephalitis
HSV Type 2 Encephalitis
Varicella-Zoster Virus Encephalitis
CMV
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Rabies
HIV
Progressive Multifocal Leukoencephalopathy
Subacute Sclerosing Parencephalitis
Arthropod Borne Viral Encephalitis
Microscopic Findings:
o Lymphocytic meningoencephalitis
o Perivascular cuffing
o Multiple foci of necrosis of gray and white matter single-cell neuronal
necrosis with phagocytosis of the debris (neuronophagia)
o Microglial nodules
o Necrotizing vasculitis with associated focal hemorrhages
Characteristically, there is a lymphocytic meningoencephalitis (sometimes with
neutrophils), and a tendency for inflammatory cells to accumulate perivascularly.
Multiple foci of necrosis of gray and white matter are found in particular, there is
evidence of single-cell neuronal necrosis with phagocytosis of the debris
(neuronophagia). Microglial cells form small aggregates around foci of necrosis,
called microglial nodules. In severe cases there may be a necrotizing vasculitis with
associated focal hemorrhages.
Inflammatory cells to accumulate perivascularly
Microglial cells form small aggregates around foci of necrosis, called microglial
nodules. In severe cases there may be anecrotizing vasculitis with associated focal
hemorrhages.
HSV-1
Herpes simplex virus type 1 (HSV-1) encephalitis is most common in
children and young adults
10% with history of prior herpes
Common presentations: alterations in mood, memory, and behavior.
HSV-1 encephalitis follows a subacute course with clinical manifestations
(weakness, lethargy, ataxia, seizures) that evolve during a more protracted
period (4 to 6 weeks)
Polymerase chain reaction (PCR based methods for virus detection in CSF samples
have increased the ease of diagnosis and the diagnosis and the recognition of a
subset of patients with less severe disease. Antiviral agents now provide effective
treatment in many cases, with a significant reduction in the mortality rate.
Inferior and medial regions of the temporal lobes and the orbital gyri og the
frontal lobes
Necrotizing and often hemorrhagic
Perivascular inflammatory infiltrates are usually present
Cowdry type A intranuclear viral inclusion bodies in both neurons and glia
This encephalitis starts in, and most severely involves, the inferior and medial regions
of the temporal lobes and the orbital gyri of the frontal lobes. The infection is
necrotizing and often hemorrhagic in the most severely affected regions. Perivascular
inflammatory infiltrates are usually present, and Cowdry type A intranuclear viral
inclusion bodies may be found in both neurons and glia. In individuals with slowly
evolving HSV-1 encephalitis, there is more diffuse involvement of the brain
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.
HSV-2
Meningitis- Adults
Encephalitis neonates
Can develop during passage through birth canal
Acute hemorrhagic and necrotizing encephalitis in immunosupreses
individual
Herpes simplex virus type 2 (HSV-2) also infects the nervous system in adults it causes
meningitis, but as many as 50% of neonates born by vaginal delivery to women with
active primary HSV genital infections acquire the infection during passage through
the birth canal and develop severe encephalitis. In the face of active HIV infection,
HSV-2 may cause an acute, hemorrhagic, necrotizing encephalitis.
VZV
Shingles
Postherpetic Neuralgia
Granulomatous Arteritis
Encephalitis with numerous sharly circumscribed lesions with
demyelination and necrosis
Primary varicella infection presents as one of the childhood exanthems (chickenpox),
ordinarily without any evidence of neurologic involvement. Following the cutaneous
infection, the virus enters a latent phase within sensory neurons of the dorsal root or
trigeminal ganglia. Reactivation of infection in adults (shingles) usually manifests as
a painful, vesicular skin eruption in a single or limited dermatomal distribution.
Herpes zoster reactivation is usually a self-limited process, but there may be a
persistent postherpetic neuralgia syndrome particularly after age 60, including both
persistent pain as well as painful sensation following nonpainful stimuli. Overt CNS
involvement with herpes zoster is much rarer but can be severe. Herpes zoster has
been associated with a granulomatous arteritis; immunocytochemical and electron
microscopic evidence of viral involvement has been obtained in a few of these cases.
In immunosuppressed individuals, herpes zoster may cause acute encephalitis with
numerous sharply circumscribed lesions characterized by demyelination followed by
necrosis.
Cytomegalovirus
Occurs in fetuses and immunosuppressed individuals
Periventricular necrosis that produces severe brain destruction
Microcephaly
Periventricular calcification
Subacute encephalitis most common pattern
Paraventricular subependymal regions of the brain Hemorrhagic
necrotizing Ventriculoencephalitis and a choroid plexitis.
Lower spinal cord and roots radiculoneuritis
Diagnosis:
o Prominent cytomegalic cells with intranuclear and intacytoplasmic
inclusions
o IHC
In the immunosuppressed individual, the most common pattern of involvement is
that of a subacute encephalitis, which may be associated with CMV inclusion-bearing
cells
Although any type of cell within the CNS (neurons, glia, ependyma, endothelium) can
be infected by CMV, there is a tendency for the virus to localize in the paraventricular
subependymal regions of the brain. This results in a severe hemorrhagic necrotizing
ventriculoencephalitis and a choroid plexitis. The virus can also attack the lower
spinal cord and roots, producing a painful radiculoneuritis. Prominent cytomegalic
cells with intranuclear and intracytoplasmic inclusions can be readily identified by
conventional light microscopy and confirmed as CMV by immunohistochemistry.
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Poliomyelitis
Meninges (aseptic meningitis)
Lower motor neurons of the spinal cord
o Flaccid paralysis
o Muscle wasting
o Hyporeflexia
o Muscle atrophy
o Contracture fibrosis
Death can occur from paralysis of the respiratory muscles acute phase
Severe respiratory compromise may occur and cause long-term morbidity
Post-polio syndrome
o Progressive weakness with decreased muscle mass and pain
The polio virus selectively infects and advances to involve the spinal cord innervations
of the diaphragm and intercostals muscles. Post polio syndrome can develop in
patients 25 to 35 years after the resolution of the initial illness. It has unclear
pathogenesis.
Microscopic findings:
Acute
o Perivascular cuffs and neuronophagia of the anterior-horn motor
neurons of the spinal cord
o Cavitation
o The cranial motor nuclei are sometimes involved
Chronic and symptomatic postmortem
o Loss of neurons and gliosis
o Residual inflammation
o Atrophy of the anterior (motor) spinal roots
o Neurogenic atrophy of denervated muscle
Acute cases show mononuclear cell perivascular cuffs and neurophagia of the
anterior-horn motor neurons of the spinal cord. The inflammatory reaction is usually
confined to the anterior horns but may extend into the posterior horns, and the
damage is occasionally severe enough to produce cavitations. In situ reverse
transcriptase RPCP has shown poliovirus RNA in anterior-horn cell motor neurons.
The cranial motor nuclei are sometimes involved. Postmortem examination in long-
term survivors of symptomatic poliomyelitis shows loss of neurons and gliosis in the
affected anterior horns of the spinal cord, some residual inflammation, atrophy of
the anterior (motor) spinal roots, and neurogenic atrophy of denervated muscle.
Rabies
Maximally affects the basal ganglia, hippocampus, brainstem and spinal
cord
Virus enters the cns by ascending along the peripheral nerves from the
wound site
Incubation period (commonly between 1 and 3 months)
Initial symptoms
o Headache
o Malaise
o Fever
o Local paresthesias around the wound
Late Manifestations
o Cns excitability
o Convulsions
o Aversion to swallowing even water (hydrophobia)
o Meningismus
o Flaccid paralysis
o Periods of alternating mania and stupor
Depends on the distance between the wound and the brain
Death is due to respiratory failure
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Rabies is a severe encephalitis transmitted to humans by the bite of a rabid animal or
even without a known bite, can also lead to rabies. Negri bodies, the pathognomonic,
microscopic finding, are cytoplasmic, round to oval, eosinophilic inclusions that can
be found in pyramidal neurons of the hippocampus and Purkinje cells of the
cerebrum, sites usually devoid of inflammation.
The red cytoplasmic inclusion body seen here is a Negri body in a Purkinje cell of the
cerebellum as a consequence of the infection with rabies virus. The virus tracks along
nerves from the site of the bite from an infected animal back to the central nervous
system. The hippocampal neurons and the cerebellar Purkinje cells are the places
Negri bodies are moste likely to appear.
Eosinophilic Negri body of raboes, also basophilic inclusions of CMV
HIV Encephalitis
Subacute encephalitis characterized by small nodules composed of
demyelination, reactive astroglial proliferation and infiltration by
lymphocytes and microglial cells
HIV associated Dementia
Early and acute phase
o Mild lymphocytic meningitis
o Perivascular inflammation
o Some myelin loss in the hemispheres
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