Difference between revisions of "CNS Response to Injury - Pathology"

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

Latest revision as of 15:12, 8 March 2011