CNS GENERAL REACTIONS TOINJURY

Reid Hefner, M.D.Department of Pathology and Anatomical

SciencesTuesday, November 7, 2017

LEARNING OBJECTIVES

• Review normal gross CNS anatomy• Be familiar with normal cells in CNS• Know special stains used in neuropathology• Understand basic CNS reactons to injury• Know in what conditons a reacton occurs • Know defnitons discussed in lecture

REFERENCES

• Robbins Basic Pathology. Kumar et al.Pathologic Basis of Disease. 9th Editon.Saunders, Philadelphia, 2015. Chapter 28.

• Robbins 9th editon, 2013, Chapter 22• Or Robbins 10th editon, 2017, Chapter 23

MACROSCOPIC EXAM

• The enlarged brain– Difuse=edema– Hydrocephalus-early*– Mass lesion(s)– May create increased intracranial pressure

• The small brain– Atrophic processes

• Hydrocephalus-late*– Destructve processes

• The focal lesion– Infarcts

BRAIN EDEMA

normal

edema

Compare the ventricles for sizeCompare the sulci for width

Brain edema-CT scan

Ventricles are slit-like

BRAIN EDEMA

Widened gyri

Narrow sulci

BRAIN EDEMA-CAUSES

• Trauma• Tumor• Stroke• Metabolic• Infecton

BRAIN EDEMA-MECHANISMS

• Cytotoxic-intracellular– Membrane permeability is increased

• Vasogenic-extracellular– Leaky hose=↑ vascular permeability

• Transependymal-extracellular– Increased ventricular pressure

CYTOTOXIC EDEMA

Cells appear vacuolated

Intracellular fluid

VASOGENIC EDEMA

The leaky pipe principle

VASOGENIC EDEMA

• Most common type• Located mainly in white

mater– Cytotoxic in gray mater

• Causes– Tumor– Stroke– Abscess– Trauma

What is wrong?

HYDROCEPHALUS

• Acute or chronic• High pressure

– Block in ventricular fow– Block in meningeal circulaton– Block in reabsorpton

• Normal pressure– Hydrocephalus Ex vacuo

About 500 ml CSFproduced each day

Ventral brain

Brain-lateral view

CSF drainage system

HYDROCEPHALUS

CLINICAL PROBLEM OFDILATED VENTRICLES

Hydrocephalus vs atrophy

TRANSEPENDYMAL EDEMA

• Rapid elevaton ofventricular pressure

• Fluid crosses ependymalbarrier

• Concentrated aroundventricles

• Brain is large

MASS LESIONSThe brain is enlarged

Cerebral Hemorrhage

BRAIN EDEMA/HYDROCEPHALUS/MASS LESION-CONSEQUENCES

• Raised intracranial pressure (RIP)– Diminished cerebral blood fow→ ischemia

• Herniatons– Shifs within the cranial cavity

• Compression of third nerve and cerebellar tonsils• Blood vessel damage in pons

• Pressure rises exponentally once all theextra-axial spaces are flled

HERNIATIONSComplicatons of edema and/or mass

Uncal herniaton

Increased intracranial pressure

Fixed dilated pupilParasympathetic fibers compromised

Pressure on third cranial nerve

What’s happening here?

IIP-DURET HEMORRHAGES

• Downward movement ofpons

• Stretching of the pontnevessels

• Secondary brainstemhemorrhages result

• Coma, death ensue

RAISED IP-TONSILLAR HERNATION

Herniation throughforamen magnum

Compression ofmedulla

RAISED IP-TONSILLAR HERNATION

Herniation intoforamen magnum

Compression ofmedulla

RIP and EDEMA-TREATMENT

• Shuntng of CSF from ventricles• Acetazolamide

– Reduce CSF producton (temporary)• Mannitol

– Osmotcally remove fuid from brain• Cortcosteroids

– Works in vasogenic edema– Reduces synthesis of prostaglandins– Seems to reduce vascular dilaton and permeability

ATROPHIC BRAINAlzheimer’s Disease

Widened sulci

Normal sulci

ATROPHIC BRAIN Alzheimer’s Disease

Hydrocephalus ex vacuo

Normal ventricles

DESTRUCTIVE LESIONSOld Infarct

FOCAL LESIONSLacunar Infarcts

MICROSCOPIC EXAM

• Neurons• Axons • Neuropil and myelin• Glia• Ependyma • Meninges

CELLULAR REACTIONS

• Injury or death• Regeneraton • Proliferaton or hyperplasia• Atrophy or cell loss• Inclusions• Storage• Neoplasia

SPECIAL STAINS INNEUROPATHOLOGY

• Nissl (cresyl violet)– Ribosomes in neurons

• Luxol fast blue (LFB)– Myelin stains blue

• PTAH-not used anymore– Astrocytc processes stained with metallic tungstc acid

• Cajal (Nobel Prize)-not used diagnostcally– Gold impregnaton for astrocytes

• Silver stains (e.g. Bodian)– Nerve processes– Several types of inclusions, senile plaques

Cast of characters

• Nero the neuron• Astrocyte• Oligodendroglia• Microglia• Pac(man) the macrophage• Expendable the ependymal

cell

Cells of the brain

Nero the neuron

I’m pretty special because I’m like an emperor

All cells pay homage to me-astrocytes dote on me

Pear-shaped histologically

Too lazy to have offspring-no regeneration

Olive the oligodrocyte

Loves myelinMakes and maintains

Myelin

Aster the astrocyte

Dotes on Nero

Provides support to Nero

Has offspring=proliferation during injury

Mike the microglia

Fights his way between theendothelial cells and the glial cells

Battles disease and the Democrats

Cast of characters

Pac(man) the macrophage

Pretty feisty

Eats everything in sight

Expendable the ependymal cell

This boring cell doesn’t react much

NEURONS

• Cells do not regenerate or proliferate– But axon may regenerate or sprout

• Necrosis• Apoptosis• Atrophy• Chromatolysis• Inclusions• Storage

NORMAL NEURON

Vesicular nucleusProminent nucleolusAbundant ribosomesAxonMicrofilaments/tubulesSynapses

NORMAL NEURON

Pear-shaped

Nissl substance

Nucleolus

Not all neurons are created equal

Internal granular layer

NISSL SUBSTANCE

Rough ER

NORMAL NEURON

Silver stain (Bodian) shows Neuroflaments and neurotubules neuronal processes

ACUTE NEURONAL INJURY

apoptosis

necrosis

normal

Mechanisms of Cell DeathFrequently inter-related

• Reduced energy– ↓ ATP, glucose, oxygen

• Mitochondrial damage– May lead to apoptosis

• Membrane damage– ↑ permeability

• Free radicals

INCLUSIONS

• Accumulatons of virus or proteins• Causes

– Misfolding of normal protein– Accumulaton of abnormal protein– Autophagic actvity

• Ofen seen as hyaline or flamentous material withincell– Usually eosinophilic in H&E stains– Glassy and homogeneous

NEURONAL ATROPHY

Atrophy in aging

INCLUSIONS

viral

tangle

Neurofibrillary tangle

AUTOPHAGIC VACUOLES

Granulovacuolar change in hippocampus in aging

Also seen are neurofibrillary tangle and neuritic plaque

Granulovacuolar change

AUTOPHAGYGranulovacuolar change

• Debris in cell• Then surrounded

by membrane• Fuses with

lysosome to formautophagic vacuole

• Debris may bedegraded/removed

• Can trigger celldeath by complex& somewhatunknownmechanism

NEURONAL STORAGE-LIPID

Tay-Sachs disease

Ganglioside storage due to hexosaminidase Adeficiency

Membranous cytoplasmic bodies

NEURONAL LOSS

Normal cerebellum

Loss of granular layer cells andPurkinje cells

AXONS AND DENDRITES

• Wallerian degeneraton• Spheroids (swollen axons)• Segmental demyelinaton• Axonal sproutng

NEURON AND PROCESSES

• Disease targets– Neuron

• Wallerian-afer neuron dies• Spheroid

– Axon• Wallerian-afer axon is cut• Spheroid

– Myelin• Demyelinaton

WALLERIAN DEGENERATION

• Severe axonal injuryor afer neuron dies

• Changes occur distalto injury

• Axonal atrophy &break-up of myelin

Myelin stain

WALLERIAN DEGENERATION

• Axon shrinks (blackarrow)

• Myelin debris withphagocytosis

ALS-Tract degeneraton

Rob. Fig. 28-39

LFB stain

AXONAL SPHEROIDS

• Axon swollen• Causes-sublethal injury

– Trauma– Aging– Near an infarct– Toxins

• Vincristne

Bodian silver stain

AXONAL SPHEROIDS

• Axonal transport slows/stops• Distended axon• Myelin may be intact, at least

early• Axons contain

– ↑ Filaments– Other organelles accumulate– Debris collects

Peripheral Nerve Injury

• Segmental demyelinaton=primary myelin disease– Remyelinaton with onion bulbs

• Axonal injury– May be secondary to myelin loss– May be Wallerian with axonal atrophy

• Myelin ovoids– May produce spheroids– Ofen induces axonal sproutng

• This probably also occurs in CNS too

Teased nerve fbers

Axons stained withosmium

PERIPHERAL NERVE-TEASED FIBERS

Myelin stained with osmium tetroxide (black)

Normal (1), demyelinated (2) and remyelinated axons (3)

1

2

Segmental Demyelinaton

• Segments of myelin lost– Between internodes

typically• Causes

– Guillain-Barré syndrome– Diabetes

REMYELINATION

NORMAL NERVE

ONION BULBS

Schwann cells proliferateEncircle demyelinated axon

Onion bulb

Rob. Fig. 27-5

Spiraling Schwann cells

AXONAL INJURY WITH MYELINOVOIDS

Myelin breaks down (ovoids) after axonal injury

More diffuse, not segmental

Axonal sproutng

Axon injury

NEUROPIL AND MYELIN

• Neuropil is the background in the grey mater– Neuritc plaques– Spongiform change

• Myelin is abundant in the white mater– Primary demyelinaton-multple sclerosis– Secondary demyelinaton-infarcton

NEUROPIL

Senile (neuritc) plaque (Bodian) CJ Disease (spongiform)

MYELIN

MS plaque

NORMAL LFB STAIN

ASTROCYTES

• Proliferate to form a glial scar– Increased cellularity (see only nuclei)

• Cytoplasmic swelling (gemistocytes)• Elaboraton of processes• Inclusions

– Rosenthal fbers, Alzheimer II cells • Neoplasia

NORMAL ASTROCYTE

CAJAL GOLD STAIN

STARS IN SKY

NORMAL GLIA

Oligos look likelymphocytes

Astrocytes havelarger, vesicular(open) nuclei

ASTROCYTES

Glial fbrillaryAcidic protein (GFAP)

GLIOSISCNS’s answer to fbrosis

Increased astrocytes seen as increased numbers of nuclei

GLIOSIS

Gemistocytes ([Gr] gemistos)Astrocyte cytoplasm is “swollen or hypertrophic”

Seen in early gliosis but can remain for months

Gemeste or Greek stuffed pepper

FIBRILLARY GLIOSIS

Glial processes form a scar (PTAH)

ASTROCYTE INCLUSIONS

Rosenthal fbersSeen in long term gliosis, especially inbenign childhood astrocytomas

Masses of intermediate filaments

Contain αβ-crystalline and ubiquitin

Alzheimer type II astrocytes

Nothing to do with Alzheimer’s diseaseType of reactive astrocyte seen in hepatic diseaseNucleus enlarged and clear

ASTROCYTE type II INCLUSIONS

Alz II cell

Seen in liver diseasewith ↑ serum NH3

Nucleus enlarged, clear,contains glycogen

Alzheimer I cell larger,multiple nuclei, visiblecytoplasm

OLIGODENDROGLIA

• Make and maintain myelin• Limited regeneraton/Limited remyelinaton• Vacuolizaton• Inclusions• Damage and loss→demyelination

– Ischemia, MS, PML• Neoplasia

OLIGODENDROCYTES

Major dense line (dark)=inner membrane

Intraperiod line=extracellular space

OLIGODENDROCYTES

LFB stain showing myelinated areas

OLIGODENDROCYTES

Satellite oligos

Near neurons

Rows of oligos in white matter

NORMAL BRAIN

OLIGODENDROCYTES

Cytoplasmic vacuoles in (cytotoxic) edema

OLIGODENDROCYTES

Intranuclear viral inclusions in PML

OLIGODENDROCYTENecrosis

Eosinophilic cytoplasm with fuzzy nucleus

MICROGLIA

• Derived mainly from monocytes inblood

• Begin as rod cells→ giter cells• Proliferate at site of injury• Difuse in large lesions• Focal lesions

– Neuronophagia– Glial nodules

MICROGLIAThe “Unglia”-Not really glia

Monocytes enter brain from blood

MICROGLIA

Rod cells frstFlaten out to travelbetween axons andother cell processes

Pacman the macrophage

Pac Man eats everything in sight

PHAGOCYTIC MICROGLIA

Gitter cells (macrophages)

Cytoplasm resembles a lattice

MICROGLIA

Neuronophagia Glial nodulesPhagocytotosis of neurons in apoptosis Focal clusters of microglia et al

EPENDYMAL CELLSThe pathologically boring cell that doesn’t react much

• Ependyma keeps CSF within ventricles• Limited regeneratve or reactve potental• Cell loss

– Hydrocephalus, infecton– Ependymits granularis (actually astrocytc gliosis)

• Infecton/infammaton– From meningits– CMV infecton

• Neoplasia

NORMAL EPENDYMA

Ciliatedepithelium

EPENDYMAL CELLS

Ependymits granularis Proliferaton of subependymal astrocytesSeen afer hydrocephalus or infammaton of the ventricles

CMV infecton of ependyma

CMV loves ependyma

Intranuclear andcytoplasmic inclusions

MENINGES: DURA AND PIA-ARACHNOID

• Blood or infammatory cells may beseen in these spaces

• Fibrosis of the leptomeninges• Tumors

– Meningiomas

MENINGES

Pia-arachnoid (leptomeninges)

Focal hyperplasia ofarachnoid

Derived from neuralcrest

MENINGEAL FIBROSIS

• Causes– Aging– Meningits– Bleeding

• Consequences– Slows CSF circulaton or

reabsorpton– May result in

hydrocephalus

MENINGESMeningioma

THE END

Raymond Cajal

Franz Nissl

Augustus Waller

del Rio Hortega