CNS Response to Injury - Pathology

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()Map NERVOUS SYSTEM (Map)



Introduction

  • The CNS is composed of two major cell types:
    1. Neurons
    2. 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:
    1. Acute Necrosis
    2. Chromatolysis
    3. Wallerian Degeneration
    4. 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:
        1. Failure of the Na+/K+pumps, causing cell swelling and an increase in extracellular potassium.
        2. 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:
    1. Ischaemia
      • For example, seizure-related ischaemia in dogs.
    2. Polioencephalomalacia in ruminants
      • Also called cerebrocortical necrosis or CCN.
    3. Salt poisoning in swine
    4. 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.

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 horses (equine dysautonomia).

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.

View images courtesy of Cornell Veterinary Medicine

The Process of Wallerian Degeneration

  1. 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.
  2. 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.
  3. Regeneration
    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

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:
    1. Neurons
    2. Oligodendroglia
    3. Astrocytes
    4. Microglia
    5. 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.
    1. They may phagocytose cell debris to transform to gitter cells.
    2. 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:
          1. Increase in intracellular calcium
          2. Failure to control free radicals
          3. Generation of nitrogen species (e.g NO and ONOO) are the main damaging events.

Oedema

  • There are three types of cerebral oedema:
    1. Vasogenic oedema
      • Vasogenic oedema follows vascular injury.
      • Oedema fluid gathers outside of the cell.
      • This is the most common variation of cerebral oedema.
    2. 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.
    3. 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

Vascular Diseases

  • Vascular diseases can lead to complete or partial blockage of blood flow which leads to ischaemia.
    • Consequences of ischaemia depend on:
      1. Duration and degree of ischaemia
      2. Size and type of vessel involved
      3. 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++, as well as Na+ and K+.
          • The channel is also voltage dependent.
            • It is blocked in the resting state by extracellular Mg++, 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+ and K+ 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+ and K+.
          • They also activate a phoshoinositide-linked second messenger system, leading to mobilisation of intra-cellular Ca++ 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:
    1. The depolarisation caused mediates an influx of Na+, Cl- and water. This give acute neuronal swelling, which is reversible.
    2. There is a rise in intracellular Ca++.
      • This is due to:
        • Excessive direct Ca++ influx via the NMDA receptor-linked channels
        • Ca++ influx through voltage gated calcium channels following depolarisation of the neuron via non-NDMA receptors
        • Release of Ca++ from intracellular stores.
      • The rise in neuronal intracellular Ca2+ 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.