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| − | {{toplink
| + | #redirect[[:Category:Central Nervous System - Response to Injury]] |
| − | |backcolour = E0EEEE
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| − | |linkpage = Nervous System - Pathology
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| − | |linktext =Nervous System
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| − | |maplink = Nervous System (Content Map) - Pathology
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| − | |pagetype =Pathology
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| − | }}
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| − | <br>
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| − | ==Introduction==
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| − | | |
| − | * The CNS is composed of two major cell types:
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| − | *# Neurons
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| − | *# Glial cells, which include:
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| − | *#* Astrocytes
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| − | *#* Oligodendrocytes
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| − | *#* Microglial cells
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| − | *#* Ependymal cells
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| − | *#* Choroid plexus epithelial cells
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| − | * The response to injury varies with the cell type injured.
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| − | | |
| − | ==Response of Neurons to Injury==
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| − | | |
| − | * Neurons are particularly vulnerable to injury, due to their:
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| − | ** High metabolic rate
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| − | ** Small capacity to store energy
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| − | ** Lack of regenerative ability
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| − | ** Axons being very dependent on the cell body.
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| − | *** Axons cannot make their own protein as they have no Nissl substance.
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| − | *** The cell body produces the axon's protein and disposes of its waste.
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| − | *** Death or damage of the cell body causes axon degeneration.
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| − | | |
| − | * There are four ways in which neurons may react to insult:
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| − | *# Acute Necrosis
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| − | *# Chromatolysis
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| − | *# Wallerian Degeneration
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| − | *# Vacuolation
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| − | | |
| − | ===Acute Necrosis===
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| − | | |
| − | * Acute necrosis is the most common neuronal response to injury.
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| − | * Causes of actue necrosis include:
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| − | ** Ischaemia
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| − | *** Diminution of the blood supply causes a lack of nutrients and oxygen, inhibiting energy production. A decrease in the levels of ATP leads to:
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| − | ***# Failure of the Na<sup>+</sup>/K<sup>+</sup>pumps, causing cell swelling and an increase in extracellular potassium.
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| − | ***# Failure to generate NAD required for DNA repair.
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| − | ** Hypoxia
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| − | ** Hypoglycaemia
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| − | ** Toxins, such as lead and mercury
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| − | | |
| − | ====Laminar Cortical Necrosis====
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| − | | |
| − | * Laminar cortical necrosis refers to the selective destruction of neurons in the deeper layers of the cerebral cortex.
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| − | ** These neurons are the most sensitive to hypoxia.
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| − | * The laminar cortical pattern of acute necrosis occurs in several instances:
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| − | *# Ischaemia
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| − | *#* For example, seizure-related ischaemia in dogs.
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| − | *# Polioencephalomalacia in ruminants
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| − | *#* Also called cerebrocortical necrosis or CCN.
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| − | *# Salt poisoning in swine
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| − | *# Lead poisoning in cattle
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| − | * It is most likely that gross changes will not be seen. When they are visible, changes may be apparent as:
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| − | ** Oedema
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| − | *** Causes brain swelling, flattened gyri and herniation
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| − | ** A thin, white, glistening line along the middle of the cortex.
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| − | *** In ruminants, this fluoresces with UV-light.
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| − | * Ultimately the cortex becomes necrotic and collapses.
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| − | | |
| − | [http://w3.vet.cornell.edu/nst/nst.asp?Fun=F_KSsrch&kw=POLIOENCEPHALOMALACIA View images courtesy of Cornell Veterinary Medicine]
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| − | | |
| − | ===Chromatolysis===
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| − | | |
| − | * Chromatolysis is the cell body’s reaction to axonal insult.
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| − | * The cell body swells and the Nissl substance disperses.
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| − | ** Dispersal of the Nissl substance allows the cell body to produce proteins for rebuilding the axon.
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| − | * IT IS NOT A FORM OF NECROSIS.
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| − | ** It is an adaptive response to deal with the injury.
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| − | ** It can, however lead to necrosis.
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| − | * Seen, for example, in grass sickness in [[Hindgut Fermenters - Horse - Anatomy & Physiology|horses]] (equine dysautonomia).
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| − | | |
| − | [http://w3.vet.cornell.edu/nst/nst.asp?Fun=Display&imgID=13353 View images courtesy of Cornell Veterinary Medicine] | |
| − | | |
| − | ===Wallerian Degeneration===
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| − | | |
| − | * Wallerian degeneration is the axon’s reaction to insult.
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| − | * The axon and its myelin sheath degenerates distal to the point of injury.
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| − | * There are several causes of wallerian degeneration:
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| − | ** Axonal transection
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| − | *** This is the "classic" cause
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| − | ** Vascular causes
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| − | ** Inflamatory reactions
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| − | ** Toxic insult
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| − | ** As a sequel to neuronal cell death.
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| − | | |
| − | [http://w3.vet.cornell.edu/nst/nst.asp?Fun=F_KSsrch&kw=WALLERIAN View images courtesy of Cornell Veterinary Medicine] | |
| − | | |
| − | ====The Process of Wallerian Degeneration====
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| − | | |
| − | # '''Axonal Degeneration'''
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| − | #* Axonal injuries initially lead to acute axonal degeneration.
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| − | #** The proximal and distal ends separate within 30 minutes of injury.
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| − | #* Degeneration and swelling of the axolemma eventually leads to formation of bead-like particles.
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| − | #* After the membrane is degraded, the organelles and cytoskeleton disintegrate.
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| − | #** Larger axons require longer time for cytoskeleton degradation and thus take a longer time to degenerate.
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| − | # '''Myelin Clearance'''
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| − | #* Following axonal degeneration, myelin debris is cleared by phagocytosis.
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| − | #* Myelin clearance in the PNS is much faster and efficient that in the CNS. This is due to:
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| − | #** The actions of schwann cells in the PNS.
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| − | #** Differences in changes in the blood-brain barrier in each system.
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| − | #*** In the PNS, the permeability increases throughout the distal stump.
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| − | #*** Barrier disruption in CNS is limited to the site of injury.
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| − | # '''Regeneration''' [[Image:neuronalvacuolation1.jpg|thumb|right|150px|Neuronal vacuolation. Image courtesy of BioMed Archive]]
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| − | #* Regeneration is rapid in the PNS.
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| − | #** Schwann cells release growth factors to support regeneration.
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| − | #* CNS regeneration is much slower, and is almost absent in most species.
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| − | #** This is due to:
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| − | #*** Slow or absent phagocytosis
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| − | #*** Little or no axonal regeneration, because:
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| − | #**** Oligodendrocytes have little capacity for remyelination compared to Schwann cells.
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| − | #**** There is no basal lamina scaffold to support a new axonal sprout.
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| − | #**** The debris from central myelin inhibits axonal sprouting.
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| − | | |
| − | ===Vacuolation===
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| − | [[Image:neuronalvacuolation2.jpg|thumb|right|150px|Neuronal vacuolation. Image courtesy of BioMed Archive]]
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| − | | |
| − | [[Image:neuronalvacuolation2.jpg|thumb|right|150px|Neuronal vacuolation. Image courtesy of BioMed Archive]]
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| − | * Vacuolation is the hallmark of transmissible spongiform encephalopathies.
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| − | ** For example, BSE and Scrapie.
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| − | * Vacuolation can also occur under other circumstances:
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| − | ** Artefact of fixation
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| − | ** Toxicoses
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| − | ** It may sometimes be a normal feature.
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| − | | |
| − | ==Glial Cell Response to Injury==
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| − | | |
| − | * The order of susceptibility of CNS cells to injury runs, from most to least susceptible:
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| − | *# Neurons
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| − | *# Oligodendroglia
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| − | *# Astrocytes
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| − | *# Microglia
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| − | *# Endothelial cells
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| − | | |
| − | ===Astrocytes===
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| − | | |
| − | * The response of astrocytes to insult include:
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| − | ** '''Necrosis'''
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| − | ** '''Astrocytosis'''
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| − | *** An increase in the number of astrocytes (i.e. astrocyte hyperplasia).
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| − | ** '''Astrogliosis'''
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| − | *** An increase in the size of astrocytes (i.e. astrocyte hypertrophy).
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| − | ** '''Gliosis'''
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| − | *** Formation of glial fibres.
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| − | *** This is a form of scarring in the CNS.
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| − | | |
| − | ===Oligodendrocytes===
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| − | | |
| − | * Oligodendrocytes are prone to hypoxia and degeneration
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| − | * Oligodendrocytes proliferate around damaged neurons.
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| − | ** This is known as '''satellitosis'''.
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| − | * Death of oligodendrocytes causes demyelination.
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| − | | |
| − | ===Microglial Cells===
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| − | | |
| − | * Microglial cells can respond in two ways to CNS injury.
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| − | *# They may phagocytose cell debris to transform to gitter cells.
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| − | *#* Gitter cells are large macrophages with foamy cytoplasm. [http://w3.vet.cornell.edu/nst/nst.asp?Fun=F_KSsrch&kw=GITTER View images courtesy of Cornell Veterinary Medicine]
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| − | *# They may form glial nodules.
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| − | *#* These are small nodules that occur notably in viral diseases.
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| − | | |
| − | ==General Responses to Injury==
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| − | | |
| − | ===Ischaemic Damage===
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| − | | |
| − | * The CNS is particularly sensitive to ischaemia, because it has few energy reserves.
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| − | * The CNS is protected by its bony covering.
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| − | ** Despite offering protection, the covering also makes the CNS vulnerable to certain types of damage, for example:
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| − | *** Damage due to fractures and dislocation.
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| − | *** Damage due to raised intracranial pressure.
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| − | **** Raised intracranial stimulates a compensatory increase in blood flow, further raising intracranial pressure. This stimulates a further increase in blood flow, and the cycle continues until intracranial pressure is so high that blood flow is impeded.
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| − | ***** The result of this is '''ischaemia'''.
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| − | * Survival of any cell is dependent on having sufficient energy.
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| − | ** Ischaemia causes cell death by impeding energy supply to cells.
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| − | *** Cells directly affected by ischamia die rapidly.
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| − | **** For example, those suffering a failure of pefusion due to an infarct.
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| − | *** Neurons surrounding this area of complete and rapid cell death exist under sub-optimal conditions and die over a more prolonged period.
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| − | **** This area of gradual death is known as the '''lesion penumbra'''.
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| − | **** There are several mechanisms implicated in cell death in the penumbra:
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| − | ****# Increase in intracellular calcium
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| − | ****# Failure to control free radicals
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| − | ****# Generation of nitrogen species (e.g NO and ONOO) are the main damaging events.
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| − | | |
| − | ===Oedema===
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| − | | |
| − | * There are three types of cerebral oedema:
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| − | *# '''Vasogenic oedema'''
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| − | *#* Vasogenic oedema follows vascular injury.
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| − | *#* Oedema fluid gathers outside of the cell.
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| − | *#* This is the most common variation of cerebral oedema.
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| − | *# '''Cytotoxic oedema'''
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| − | *#* Cytotoxic oedema is due to an energy deficit.
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| − | *#** The neuron can’t pump out sodium and water leading to swelling within the cell.
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| − | *# '''Interstitial oedema'''
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| − | *#* Associated with hydrocephalus.
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| − | *#* This type of cerebral oedema is of lesser importance.
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| − | * One serious consequence of oedema is that the increase in size leads to the brain trying to escape the skull.
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| − | ** This causes herniation of the brain tissue.
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| − | ** The most common site of herniation is at the foramen magnum.
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| − | *** The medulla is compressed at the site of the respiratory centres, leading to death.
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| − | | |
| − | ===Demyelination===
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| − | | |
| − | * Demyelination is the loss of initially normal myelin from the axon.
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| − | * Demyelination may be primary or secondary.
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| − | | |
| − | ====Primary Demyelination====
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| − | | |
| − | * Normally formed myelin is selectively destroyed; however, the axon remains intact.
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| − | * Causes of primary demyelination:
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| − | ** Toxins, such as hexachlorophene or triethyl tin.
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| − | ** Oedema
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| − | ** Immune-mediated demyelination
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| − | ** Infectious diseases, for example canine distemper or caprine arthritis/encephalitis.
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| − | | |
| − | ====Secondary Demyelination====
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| − | | |
| − | * Myelin is lost following damage to the axon.
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| − | ** I.e. in [[CNS Response to Injury - Pathology#Wallerian Degeneration|wallerian degeneration]]
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| − | | |
| − | ===Vascular Diseases===
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| − | | |
| − | * Vascular diseases can lead to complete or partial blockage of blood flow which leads to ischaemia.
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| − | ** Consequences of ischaemia depend on:
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| − | **# Duration and degree of ischaemia
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| − | **# Size and type of vessel involved
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| − | **# Susceptibility of the tissue to hypoxia
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| − | * Potential outcomes of vascular blockage include:
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| − | ** Infarct, and
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| − | ** Necrosis of tissue following obstruction of its blood supply.
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| − | * Causes include:
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| − | ** Thrombosis
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| − | *** Uncommon in animals but may be seen with DIC or sepsis.
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| − | ** Embolism. e.g.
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| − | *** Bone marrow emboli following trauma or fractures in dogs
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| − | *** Fibrocartilaginous embolic myelopathy
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| − | ** Vasculitis, e.g.
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| − | *** Hog cholera (pestivirus)
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| − | *** Malignant catarrhal fever (herpesvirus)
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| − | *** Oedema disease (angiopathy caused by E.coli toxin)
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| − | | |
| − | ===Malacia===
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| − | | |
| − | * Malacia may be used:
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| − | ** As a gross term, meaning "softening"
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| − | ** As a microscopic term, meaning "necrosis"
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| − | * Malacia occurs in:
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| − | ** Infarcted tissue
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| − | ** Vascular injury, for example vasculitis.
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| − | ** Reduced blood flow or hypoxia, e.g.
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| − | *** Carbon monoxide poisoning, which alters hemoglobin function
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| − | *** Cyanide poisoning, which inhibits tissue respiration
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| − | | |
| − | ==Excitotoxicity==
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| − | | |
| − | * The term "excitotoxicity" is used to describe the process by which neurons are damaged by glutamate and other similar substances.
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| − | * Excitotoxicity results from the overactivation of excitatory receptor activation.
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| − | | |
| − | ===The Mechanism of Excitotoxicity===
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| − | * '''Glutamate''' is the major excitatory transmitter in the brain and spinal cord.
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| − | ** There are four classes of postsynaptic glutamate receptors for glutamate.
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| − | *** The receptors are either:
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| − | **** Directly or indirectly associated with gated ion channels, '''OR'''
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| − | **** Activators of second messenger systems that result in release of calcium from intracellular stores.
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| − | *** The receptors are named according to their phamacological agonists:
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| − | **** '''NMDA receptor'''
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| − | ***** The NMDA receptor is directly linked to a gated ion channel.
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| − | ***** The ion channel is permeable to Ca<sup>++</sup>, as well as Na<sup>+</sup> and K<sup>+</sup>.
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| − | ***** The channel is also voltage dependent.
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| − | ****** It is blocked in the resting state by extracellular Mg<sup>++</sup>, which is removed when membrane is depolarised.
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| − | ***** I.e. both glutamate and depolarisation are needed to open the channel.
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| − | **** '''AMPA receptor'''
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| − | ***** The AMPA receptor is directly linked to a gated ion channel.
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| − | ***** The channel is permeable to Na<sup>+</sup> and K<sup>+</sup> but NOT to divalent cations.
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| − | ***** The receptor binds the glutamate agonist, AMPA, but is not affected by NMDA.
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| − | ***** The receptor probably underlies fast excitatory transmission at glutamatergic synapses.
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| − | **** '''Kainate receptor'''
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| − | ***** Kainate receptors work in the same way as AMPA receptors, and also contribute to fast excitatory transmission.
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| − | **** '''mGluR''', the '''metabotropic receptor'''
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| − | ***** Metabotropic receptors are indirectly linked to a channel permeable to Na<sup>+</sup> and K<sup>+</sup>.
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| − | ***** They also activate a phoshoinositide-linked second messenger system, leading to mobilisation of intra-cellular Ca<sup>++</sup> stores.
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| − | ***** The physiological role ot mGluR is not understood.
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| − | | |
| − | * Under normal circumstances, a series of glutamate transporters rapidly clear glutamate from the extracellular space.
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| − | ** Some of these transporters are neuronal; others are found on astrocytes.
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| − | * This normal homeostatic mechanism fails under a variety of conditions, such as ischaemia and glucose deprivation.
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| − | ** This results in a rise in extracellular glutamate, causing activation of the neuronal glutamate receptors.
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| − | * Two distinct events of excitiotoxicity arise from glutamate receptor activation:
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| − | *# The depolarisation caused mediates an influx of Na<sup>+</sup>, Cl<sup>-</sup> and water. This give '''acute neuronal swelling''', which is reversible.
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| − | *# There is a '''rise in intracellular Ca<sup>++</sup>'''.
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| − | *#* This is due to:
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| − | *#** Excessive direct Ca<sup>++</sup> influx via the NMDA receptor-linked channels
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| − | *#** Ca<sup>++</sup> influx through voltage gated calcium channels following depolarisation of the neuron via non-NDMA receptors
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| − | *#** Release of Ca<sup>++</sup> from intracellular stores.
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| − | *#* The rise in neuronal intracellular Ca<sup>2+</sup> serves to:
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| − | *#** Uncouple mitochondrial electron transport and activate nitric oxide synthase and phospholipase A, leading to generation of reactive oxygen and nitrogen species which damage the neurone.
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| − | *#** Activats a number of enzymes, including phospholipases, endonucleases, and proteases.
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| − | *#*** These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.
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| − | * Excitotoxicity is, therefore, a cause of acute neuron death.
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