CNS Response to Injury - Pathology

()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 (granular cytoplasmic reticulum and ribosomes found in nerve cell bodies) 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.
     • Gitter cells are large macrophages with foamy cytoplasm. View images courtesy of Cornell Veterinary Medicine
  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

• Myelin is lost following damage to the axon.
  • I.e. in 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:
    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.