Pathology of the Central Nervous System 2A2016

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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-Lizlie,Georgia,Kat,Tata, Arvee- Special Thanks to Kuya Cliff and Nickie..

- 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,

20 | P a g e


***these small cavitary infarcts are just a few mm wide (

21 | P a g e


***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

22 | P a g e


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

23 | P a g e


- 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

24 | P a g e


***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

25 | P a g e


- 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

26 | P a g e


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

27 | P a g e


- 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

28 | P a g e


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

29 | P a g e


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.

30 | P a g e


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

31 | P a g e


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

32 | P a g e


- 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)

33 | P a g e


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:

34 | P a g e


- 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)

35 | P a g e


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

36 | P a g e


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

37 | P a g e


- 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

38 | P a g e


- 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

39 | P a g e


- 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

40 | P a g e


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

41 | P a g e


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.

42 | P a g e


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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-Lizlie,Georgia,Kat,Ta

Documents

Pathology of the Central Nervous System 2A2016