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PATHOLOGY OF CENTRAL NERVOUS

SYSTEM

Yekti W. Widjono

Central Nervous System

CONGENITAL

INFECTION

NEOPLASM

CEREBROVASCULAR

TRAUMA

PRINTED BY FILAMEN '05Focal polymicrogyria: An incidental finding in a neurologically normal, 86-year-old man who died of chronic lung disease

CNS Infections: Routes

1. Direct - skull fracture

2. Extension - sinuses and ears

3. Blood dissemination

4. Peripheral nerves (viruses)

Some definitions

Pachymeningitis: inflammation of dura

Leptomeningitis (meningitis): infl of arachnoid

Cerebritis: infection of brain parenchyma by

agents other than viruses

Encephalitis: infl of parenchyma by viruses

Acute meningitis: pathology

Bacterial: infiltration by neutrophils

Viral (aseptic): infiltration by lymphocytes

Fungus: predominantly infiltration by lymphocytes

Infiltration more common at base of brain than at

convexity

Acute purulent meningitis: causative organisms

Neonatal: E. coli, B. strepto, L. monocytogenes

Children: H. influenzae, S. pneumoniae

Adolescents: N. meningitidis (meningococcus)

Adults: S. pneumoniae

Acute bacterial meningitis: complications

Hydrocephalus, if not resolved

Pyocephalus (pus in ventricle)

Thrombosis of meningeal vessels and infarcts

Cerebritis and abscess

Aseptic meningitis

Resolves spontaneously

No permanent sequela

Viruses:

Mumps, coxsackie, echo

Chronic meningitis: pathology

Organisms: mycobacteria, fungus, spirochettes

Infiltration by lymphocytes

Granulomas: tuberculosis, fungus

Complications

fibrosis at base of brain hydrocephalus (more common than in bacterial

infection) Resolves spontaneously

Aspergillosis

1. Opportunistic infection

2. Primary pulmonary infection

3. Cerebritis, abscess, infarctions

4. Vascular invasion

Candidosis

1. Opportunistic infection

2. Primary GI infection

3. Microabscesses

4. Most common CNS fungal

infection at autopsy

Cryptococcosis

1. Most common clinical CNS mycosis

2. Primary lung infection

3. Majority spontaneous infection

4. 30% opportunistic infections

5. Minimal inflammation

6. Multiple cysts: honey-comb appearance

7. India-ink exam of CSF

Phycomycosis

1. Mucormycosis common

2. Associated with:

Diabetic ketoacidosis

Intravenous drug abuse

3. Acute fulminant disorder

Bacterial Parenchymal Infections

Cerebritis

Brain abscess

Brain Abscess: Sites

1. Direct extension:– large; single– frontal lobe in frontal sinusutis– temporal lobe in otitis and mastoiditis

2. Embolic:

small; multiple

MCA territory common

Cerebral Abscess:Pathology

1. Suppurative cerebritis

2. Abscess formation

3. Granulation tissue

4. Fibrous capsule

Encephalitis: Viral Tropism

1. Coxsackie, Echo, Mumps: Meninges

2. Herpes simplex: Temporal lobes

3. Herpes zoster (varicella): Posterior

ganglia

4. Poliomyelitis: Motor neurons

5. Rabies: Hippocampus, cerebellum

6. JC virus (PML): Oligodendrocytes

Acute viral encephalitis: Pathology

Lymphocytic infiltration

Perivascular lymphocytes

Microglial nodules

Inclusion body

Necrosis

Viral inclusion bodies: sites

HSV: intranuclear in neurons and oligodendrocytes

Rabies: intracytoplasmic in neurons

Cytomegalovirus: intranuclear or intracytoplasmic in neurons, glial cells, ependyma

PML: intranuclear in oligodendrocytes

Slow Virus Infections: TypesConventional viruses:

1. Progressive multifocal leukoencephalopathy (PML)

PAPOVA viruses

2. Subacute sclerosing panencephalitis (SSPE)Measles virus

3. Progressive rubella encephalopathyRubella virus

Unconventional agents:Spongiform Encephalopathies (PRION

diseases)

Pathologic States Associated with Progressive

Multifocal Leukoencephalopathy

Lymphoma

Leukemia

Sarcoidosis

Carcinomatosis

Miliary tuberculosis

Organ transplants (kidney)

Transmissible Spongiform Encephalopathies (PRION diseases)

Animals:

Scrapie - sheep, goat

Transmissible mink encephalopathy

Chronic wasting disease - mule deer, elk

Feline spongiform encephalopathy

Bovine spongiform encephalopathy (BSE)

Humans (subacute spongiform encephalopathy):

Creutzfeldt-Jacob disease (CJD)

Gerstmann-Straussler Syndrome - Fam AD

Fatal familial insomnia - Fam AD

Please read from the book on:

HIV infection (AIDS)

Cytomegalovirus

Toxoplasmosis

BRAIN NEOPLASM

General Considerations1. Comprise: 10% of all tumors

2. Most common childhood neoplasms

3. Peak incidence at 5th decade

4. Supratentorial tumors in adults

5. Infratentorial tumors in childhood

6. Different tumors in different ages

7. Primary tumors – infiltrative Metastatic - well-demarcated

8. Intraneural seeding occur, but no extraneural metastasis

9. Produce neurologic symptoms by size,location,invasiveness, and secondary effects

Varieties of brain tumors

Meninges: meningioma, hemangiopericytoma

Astrocytes: astrocytoma (various types)

Oligodendrocytes: oligodendroglioma

Ventricles: ependymoma, choroid plexus papilloma,

colloid cyst

Vascular: hemangioblastoma

Primitive cells: germinoma, medulloblastoma,

neuroblastoma, pineoblastoma, retinoblastoma

Neuronal: ganglioglioma, gangliocytoma

Pituitary: adenoma, craniopharyngioma

Nerves: schwannoma, neuroblastoma

Astrocytes: astrocytoma (various types)

Oligodendrocytes: oligodendroglioma

Ventricles: ependymoma, choroid plexus

papilloma, colloid cyst

GLIOMA

Incidence of Intracranial Gliomas (All ages)

Glioblastomas

Astrocytomas

Ependymomas

Medulloblastomas

Oligodendrogliomas

Choroid plexus papillomas

Colloid cysts

Incidence of Primary IntraspinalIntramedullary Gliomas

Ependymomas

Astrocytomas (grades 1 and 2)

Glioblastomas (Astrocytomas

grades 3 and 4)

Oligodendrogliomas

Other tumors

Frequent Brain Tumors

Meningioma

Astrocytoma/glioblastoma

Oligodendroglioma

Ependymoma

Medulloblastoma

Schwannoma/neurofibroma

Phakomatosis

Meningioma

Arachnoid cells origin

Attached to dura, subdural

Common sites: parasagittal (falx),

sphenoidridge, olfactory groove

Female:Male 3:2 or 2:1

Changes in cranium

Hyperostosis

Invasion

Microscopic: whorls and psammoma bodies

Menoingioma

Meningothelail whorls

Psammoma bodies

Gliomas

Astrocytes- astrocytomas

Fibrillary

Pilocytic

Oligodendrocytes- oligodendrogliomas

Ependyma- ependymomas

Astrocytomas

Supratentorial

Malignant

Fibrillary

Childhood

Infratentorial

Cystic

Benign

Pilocytic

Fibrillary Astrocytomas

Grossly solid

Common in cerebral hemispheres

Low grade in young, higher

grade in older

Grading

Astrocytoma (low grade)

Anaplastic astocytoma

Glioblastoma multiforme

Fibrillary Astrocytoma: microscopic

Low grade- hypercellularity, pleomorphism

Anaplastic- as above plus mitosis, vascular

endothelial proliferation

Glioblastoma multiforme- as above plus

necrosis and pseudopalisades. Grossly

variegated appearance (multiforme)

Astrocytoma

Glioblastoma

Glioblastoma - pseudopalisade

Pilocytic AstrocytomaCommon in childhood

Most slow growing of the gliomas

Sites: cerebellum, around III V., optic

Grossly cystic with mural nodule

Microscopic

Elongated hair-like (pilo) elongated

Rosenthal fibers

Rosenthal fiber definition

Dense, eosinophilic fibers within

cytoplasmic processes of astrocytes.

Correspond to aggregate accumulation of

intermediate filaments in these processes.

Pilocytic astrocytomaMural nodule

Pilocytic astrocytoma

Oligodendroglioma

Cells of origin: Oligodendrocytes

Common in cerebral hemispheres

Calcifications common among all

gliomas

Grades

Low grade

Anaplastic

Oligodendroglioma

Oligodendroglioma, calcifications

Tumors in Ventricles

1. Ependyma: Ependymoma

2. Choroid Plexus: Papilloma

Ependymomas

Arise from ependymal lining- ventricles

and central canal of spinal cord

Common in childhood

4th V. common in cerebrum

Most common tumor of spinal cord

parenchyma in adult

Microscopic

perivascular pseudorosettes

ependymal rosettes

Ependymoma

Ependymoma: perivascular pseudorosettes

Embryonal tumors(Primitive neuroectodermal tumors)

Neuroblastoma - cerebral hemispheres

Neuroblastic (neuronal) differentiation

Medulloblastoma - cerebellum

Neuronal and glial differentiation

Ependymoblastoma – ventricles

Ependymal differentiation

Pineoblastoma- pineal region

Retinoblastic differentiation

All commonly known as Primitive

neuroectodermal tumor (PNET)

Medulloblastoma

Origin: primitive neuroectodermal cells

Age: 1st decade of life. Most common

brain tumor at this age.

Site: vermis of cerebellum

May cause hydrocephalus

Subarachnoid dissemination

Medulloblastoma

Homer-Wright rosettes

Histologic Patterns: definitions

Whorls: onion-skinning pattern of tumor cells

Psammoma bodies: laminated calcium

Pseudopalisading: lining up of the tumor cells

around a central necrotic area

Palisade: lining up of tumor cells around their own

cytoplasmic processes. No necrosis.

Pseudorosette: tumor cells around blood vessels,

cells equidistant from vessel walls.

Rosettes: tumor cells around central lumen or

fibrillary area of cellular processes

Brain Tumors: Microscopic

Tumor Microscopic

Meningioma Whorls and psammoma bodies

Glioblastoma Pseudopalisades

Oligodendroglioma Mosaic/poached-egg

Ependymoma Perivascular pseudorosettes

Medulloblastoma Rosettes (Homer-Wright)

Tumors of Nerve Rootsand Peripheral Nerves

1. Schwannoma

viii Cranial nerve (Acoustic sch.)

Spinal roots, posterior

Peripheral nerves

2. Neurofibroma

Spinal Roots, rare

Peripheral nerves

3. Malignant variants

Malignant peripheral nerve sheath tumor (MPNT)

Peripheral nerve tumors

Schwannoma

Schwann cells

Compress the nerve trunk

Encapsulated

Easily resectable without nerve damage

Microscopic:

Antony A and B fibers

Verocay bodies

Neurofibroma

Schwann cells, neurites, fibroblasts

Fusiform and involves nerve trunk

Not encapsulated

Not resectable without sacrificing nerve

Micro- Intermingled cells with wavy nuclei

AcousticSchwannoma

Antony A

Antony B

Palisades

Metastatic Brain TumorsMost common brain tumor in adults.

Common primary sites: melanoma, lung,

breast, GI tract, kidney.

Most are in cerebrum (MCA territory).

In gray-white junctions due to rich capillarity

Discrete, globoid, sharply demarcated tumors.

Amenable to surgical resection.

Single or multiple.

Brain edema frequent.

Metastatic tumors

Phakomatosis : definition

Phakos (Greek): lentil mole or freckle.

Neurologic abnormalities combined with

defects of skin or retina, explained by their

common ectodermal origin.

Involvement of visceral organs

Phakomatosis(Neurocutaneous dysplasia)

1. Neurofibromatosis

(von Recklinghausen's dis.)

2. Tuberous Sclerosis

3. Sturge-Weber disease

(Encephalofacial Angiomatosis)

4. von Hippel-Lindau Disease

5. Neurocutaneous Melanosis

Neurofibromatosis

1. Dominant inheritance

2. Multiple neurofibromas

Central - CNS

Peripheral nerves

3. Increased incidence of:

Meningioma

Glioma

Schwannoma - bilateral VIII N.

4. Cafe-au-lait (melanosis) in skin

5. Elephantiasis: increased connective

tissue

Multiple neurofibromasCafé-au-lait spots

Tuberous Sclerosis

1. Dominant inheritance

2. Clinical triad:– Seizures– mental retardation– adenoma sebaceum

3. Retinal hamartoma (phakoma)

4. Tubers in cerebral cortex

5. Subependymal giant cell astrocytoma

6. Hamartomas in other organs: heart, kidney

Tubers

Adenoma sebaceum

CEREBROVASCULAR DISORDERS

Cerebrovascular diseases involve circulatory disorders of brain secondary to alterations of structural integrity of blood vessels and/or alterations of blood pressure, and the complications thereof

Cerebrovascular disease is the third leading cause of death after heart disease and cancer in developed world.

Some DefinitionsAnoxia - lack of oxygen

Ischemia - lack of circulation

Intracranial - enclosed by cranial bone (dura, arachnoid, brain)

Intracranial arteries - branches of circle of Willis in subarachnoid space (vertebro-basilar, ICA, MCA, ACA)

Intracerebral arteries/arterioles - within brain parenchyma

Intramedullary - in medulla or spinal cord

Major Types of Cerebrovascular Disease

1. Anoxia/Ischemia

2. Intracranial hemorrhage

Generalized (global)To entire brain

Focal (occlusive disease)To portion of brain

Ischemia

Sequelae of severe global ischemia

Persistent vegetative state

severe neurological impairment and deep coma

Brain death

absence of perfusion, reflexes, respiration

brain stem damage

isoelectric (flat) EEG

“respirator brain”

Conditions associated with hypotension

Myocardial infarction

Septic shock

GI hemorrhage

ruptured varices

bleeding ulcer

Ruptured aortic aneurysm

Others

Arterial

Occlusio

n: Caus

1. Atherosclerosis

2. Thrombosis

3. Embolism

4. Vasospasm

5. Extrinsic compression

Anemic infarction

Hemorrhagic infarction

Anemic and hemorrhagic infarctions vs hemorrhage

Anemic (pale, ischemic) infarction

no hemorrhage in infarcted area

Hemorrhagic infarction

petechial hemorrhage in infarcted area

no displacement of brain tissue

Hemorrhage

Bleeding is the primary event. Destroys and displaces the brain tissue

Embolic Materials

1. Thrombus: from heart; aorta; carotid

2. Atheroma: aorta; carotid

3. Septic: endocarditis

Note: Most emboli go to middle cerebral artery.

Intracranial Hemorrhage: Sites and Causes

1. Epidural

2. Subdural

3. Intracerebral

4. Subarachnoid

5. Mixed cerebral-subarachnoid

Trauma

Vascular (and trauma)

1. Intracerebral

Hypertension

2. Subarachnoid

Berry aneurysm

3. Mixed cerebral-subarachnoid

Vascular malformations

Intracranial Hemorrhage: Main Causes

Hypertensive Brain Hemorrhage: Sites

1. Putamen-Claustrum

2. Cerebral white matter

3. Thalamus

4. Pons

5. Cerebellum

Hypertensive Hemorrhage: Clinical

Presence of hypertension

Absence of prodroms

Headache frequent

Gradual or abrupt neurologic deficit

Deepening stupor or coma

Blood CSF (blood ruptures in ventricle or subarachnoid space)

Intracranial vs intracerebral arteries

Intracranial arteries – atherosclerosis

Intracerebral arteries - hypertensive disease. No atherosclerosis.

Vascular changes in hypertension

Accelerated atherogenesis in arteries

changes in arteriolesthickening and hyalinization of wall (arteriolosclerosis or arteriolar sclerosis)

Vascular changes in hypertension

Accelerated atherogenesis in arteries

changes in arteriolesthickening and hyalinization of wall (arteriolosclerosis or arteriolar sclerosis)

necrosis of vessel wall (fibrinoid necrosis)

1. Ruptured saccular (berry) aneurysm

2. Vascular malformations

3. Mycotic aneurysm (septic emboli)

4. Trauma

Causes of Subarachnoid Hemorrhage

An aneurysm is

a dilatation of wall of an artery,

a vein or the heart.

Aneurysms- Types

Saccular (berry)

Atherosclerotic (fusiform)

Mycotic (infections)

Dissecting (rare)

Berry aneurysm Occur only at circle of Willis

Arise at points of branching

Saccular structure (sac-like, berry)

Devoid of media and elastic lamina

Multiple aneurysms common

Common sites: middle cerebral, internal carotid, anterior cerebral arteries

Most common cause of non-traumatic bleeding in the subarachnoid space

Increased incidence in patients with: inherited polycyctic kidney; neurofibromatosis; Marfan syndrome; fibromuscular dysplasia; coarction of aorta.

Ruptured Aneurysm: Clinical

Sudden severe headache

Relative alertness following initial unconsciousness

No focal neurologic deficit

Bloody CSF

Vascular Malformations of brain: Types

1. Arteriovenous malformation (AVM)

2. Cavernous angioma

3. Venous angioma

4. Capillary telangiectasis

Arteriovenous malformation (AVM)

1. Abnormal thick arteries and veins

2. No intervening capillary channels

3. Arterio-venous fistula

4. Occur any part of the brain fromsurface to ventricle

5. Common type of malformationand cause of hemorrhage

Cavernous (hem)angioma

1. Dilated veins

2. Veins intercommunicate

3. No brain tissue between the veins

4. Common type of malformationand cause of hemorrhage

Venous (hem)angioma

1. Dilated veins

2. Do not communicate

3. Brain tissue present in between vessels

4. Not a common source of bleeding

Capillary telangiectasis1. Dilated capillaries

2. Not a common source of bleeding

3. Mostly incidental finding at autopsy

Clinical manifastation of cerebrovascular diseases

• Strokeor

• Cerebrovascular accident (CVA)

Stroke: variants1. Transient ischemic attacks (TIA)

deficiency resolves within 24 hours

2. Completed strokes

Causes of Stroke or CVA

1. Brain infarction

2. Brain hemorrhage

3. Subarachnoid hemorrhage

4. Miscellaneous

Stroke: Clinical differentiation

Prodromes Onset LOC CSF Blood Headache

Thrombosis TIA Gradual No No No

Embolism Cardiac Sudden No + / - + / -

Sub Hem No Sudden Initially + + + + + +

Intr Hem No Sudden Usual + + + + + Note: Lateralizing sign in all, except Subarachnoid hemorrhage.

LOC=loss of consciousness. Sub=subarachnoid. Intr=intracerebral

Cerebral Edema: Types

1. Vasogenic: fluid in extracellular spacecommon type:infarction, hemorrhage,tumor, trauma

2. Cytotoxic : fluid in intracellular spacehypoxia, ketoacidosis

Summary-1

Ischemia

Pale infarct(slow complete occlusion)

Hemorrhagic infarct(incomplete occlusion)

global (patterns of injury)

Focal vascular occlusion

Summary-2

Hemorrhage

Subarachnoidberry aneurysm (sites, structure)

Intracerebralhypertensive disease(sites, arteriolar changes)

Mixedvascular malformations (types, structure)

CENTRAL NERVOUS SYSTEM TRAUMA

Important Considerations

Location of the lesion

Limited capacity to regenerate

Shape of the object

Force of the impact

Head’s motion

Types of Injury

Open vs. closed

Penetrating vs. blunt

External vs. internal damage

Skull fractures

Parenchymal

Vascular

ConcussionClinical syndrome

Change in momentum of the head

Instantaneous transient neurologic dysfunction,

loss of consciousness, loss of reflexes

Full neurologic recovery

Amnesia

No morphological changes

Contusion

Bruising resulting from transmission of force

through other tissues

Vessel injury, tissue damage, edema

Crests of gyri

Inferior surfaces of frontal lobe, temporal

Anywhere adjacent to fractures (fracture

contusion)

PRINTED BY FILAMEN '05Fronto-temporal contusions

Remote fronto-temporalcontusions

Base of frontal lobes

Contusions

Intact brain tissue

Infarct

Contusions

Lacerations

Coup vs. Contrecoup

Coup lesion: At the site of

trauma, while head is still

Contrecoup: At the opposite

site of trauma, while head is

in motion

Epidural Hematoma

Middle meningeal artery tear

by fracture

May occur without fracture in

children

Clinical presentation several

hours after injury (lucid

interval)

Skull fracture

Fracture

Impression of middle meningealartery

DuraEpidural space

Subdural space

Epiduralhematoma

Subdural Hematoma

Bridging vein tear by sudden

movement of brain

Slowly progressive neurologic

deterioration

Evolution:

Lysis of clot (1 week)

Early organization (2 weeks)

Hyalinized connective tissue (1-3

months)

Bridging veinsReflected dura

Subdural clot

Subduralhematoma

Subdural Hematoma

Multiple recurrent

hemorrhages from delicate

granulation tissue vessels

Chronic subdural hematoma

Removal of hematoma and

subdural membrane

Chronicsubdural hematomas

Capillary

Fibroblastic/endothelialproliferation

Fibrin clot

Subdural hematoma, chronic

Internal carotidarteries

AneurysmSubarachnoidhemorrhage

Post traumatic Syndromes

Post traumatic hydrocephalus

Post traumatic dementia,

“punch-drunk” syndrome

(dementia pugilistica)

Post traumatic epilepsy,

meningioma, infection

Post traumatic psychiatric

disorders

Spinal Cord Trauma

Associated with bone injury

Progression of lesion due

to vascular injury

(ischemia) and

excitotoxicity

DISORDERS OF MYELIN

Overview

Primary myelin diseases (multiple sclerosis)

Diseases with secondary damage to myelin (HIV leukoencephalopathy, progressive multifocal leukoencephalopathy-PML,carbon monoxide poisoning)

Dysmyelinating diseases- leukodystrophies

Multiple Sclerosis (MS)

Classical MS, Charcot type

Most common demyelinating disorder

Onset rare in childhood or >50 years of age

Male:Female = 1:2

Relapsing/remitting episodes, gradual deterioration

Clinical findings do not fit into a definitive anatomical distribution

Multiple SclerosisEtiology unknown

Environmental:

Common in N. European & US, rare in orientals

15 years of age

Genetic:

15-20X risk in immediate relatives

HLA-DR2

Chemical

Multiple Sclerosis

Autoimmune myelin destruction

Experimental allergic encephalomyelitis (EAE)

Increased cytokines, leukocyte adhesion molecules on endothelial cells

CD 4+ and CD 8+ T-cells, and macrophages

Multiple Sclerosis

Most common locations: Optic nerve (unilateral visual impairment), spinal cord (motor/sensory impairment, bladder control problems), brain stem (cranial nerve deficits, ataxia)

Magnetic Resonance Imaging (MRI)

Cerebrospinal fluid

Increased immunoglobulins

Oligoclonal bands

Ventricle

Plaques

Multiple sclerosis

Plaque

Multiple sclerosisMidbrain

Aqueduct

Substantianigra

Acute MS, myelin stain

Cellular lesion,myelin loss

Residual myelin

Acute MS, silver stain

Preserved axons

Chronic plaque, myelin stain

No inflammationMyelin loss,hypocellular

Myelin insurroundingtissues

Sharp border

Chronic plaque, silver stain

Lesion border

Few preserved axons

Other Primary Demyelinating Diseases

Acute Disseminated Encephalomyelitis (ADEM; postinfectious/ perivenous/ postvaccinial encephalomyelitis):

Acute, monophasic, children and adults, with headache, lethargy, coma, rapid progression, 20 % death

Acute Necrotizing Hemorrhagic Encephalomyelitis(ANHE;Weston-Hurst Disease):

After urinary tract infection, M. pneumoniae infection, in children and young adults

Numerous petechiaein WM

ANHE, myelin stain

Capillaries

Perivascular myelinloss, inflammation

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