Peripheral Nervous System - Response to Injury

Age related changes

These changes are normal and include:

"The Axon Reaction"

While regenerative events take place in the periphery, a series of changes take place within the cell body:
- Swelling of the cell body
- Displacement of the nucleus to the edge of the cell (opposite the axon hillock)
- Dispersal of The Nissl substance, especially in the centre of the cell (hence the alternative name for this process of chromatolysis).

There is also a response by the surrounding cells, microglia and astrocytes in the CNS, and satellite cells in the sensory ganglia.
- The microglia/astrocyte response is associated with stripping of synapses from the cell body and dendrites.

All of these changes reflect a profound change in the status of the cell, from one whose function is to receive and relay information, to one in which the objective is to extend its axon and re-establish synaptic contact with its target.
At a molecular level, this involves a switch in expression of genes associated with transmission, such as the neurotransmitter genes, to the expression of genes associated with growth, such as were expressed by the cell during development (eg growth associated proteins or GAP's).

In many diseases of the PNS it can be shown both clinically and pathologically that the longest axons, and often those of greatest diameter, tend to be affected earliest in the degenerative process.
Moreover, the Wallerian degeneration starts distally and progresses in a proximal direction towards the cell body (in contrast to nerve section).
The degeneration may halt and then be followed by a regenerative response.
Changes of this nature are referred to as dying back degeneration, a good example of which is tri-ortho-phosophate poisoning:
- A particular level of exposure will cause degeneration of the axon terminals and pre-terminals within somatic muscle.
- The distance over which the axon needs to regenerate is very small and therefore recovery takes place quickly.
- Greater or more prolonged exposure will result in distal degeneration over a much longer distance.
- In this type of pathology the rate of recovery will to some extent relate to the distance over which the axon has to regenerate.
- Other toxins which induce a "dying back" pathology include acrylamide and hexacarbon solvents.

The explanation for the dying-back phenomenon comes from a realisation that the integrity of the axon depends on efficient protein synthesis in the cell body and efficient axoplasmic transport.

The milk-round analogy

If milk production is affected at the dairy (in other words, the cell is metabolically compromised) then the milk man will run out of milk before the round is finished.
The same will occur if the speed at which the milkman delivers milk is reduced so that he has to deliver more at each house.
This would be akin to disruption in axoplasmic transport.
In both examples, the cause is different but the result is the same, the folk at the end of the round, or distal axon, go without.

Generally speaking, the myelin sheath that a Schwann cell makes during development is a stable structure throughout life.
Damage to the Schwann cell, however, means that it is unable to maintain its myelin sheath which degenerates and is removed from the axon.
The exposed axon remains intact but unable to conduct impulses.
Since Schwann cells function independently of one another, this demyelinating event can take place at random along the fibre, and individual single internodes may be lost
- This process is called segmental demyelination, and is distinct from secondary demyelination, the mis-leading term to which the loss of myelin secondary to axonal injury is sometimes referred.

Segmental or primary demyelination may be quite difficult to detect on routine histology, especially distinguishing it from Wallerian degeneration.
It can be seen in:
- toluidine blue-stained
- resin-embedded sections
- teased-fibre approach, perhaps the best way to see it.

Schwann cells are not post-mitotic cells, so if an intemode is lost as a result of axonal death, new Schwann cells can be generated to replace the missing cells which then remyelinate's the exposed length of axon.
Remyelination is characterised by two key features that are related:

This means that the number of new internodes that remyelinate an exposed length of axon may be more than the original number.
Shortened internodal length can be most readily identified in teased fibre preparations, while thin sheaths can be seen is resin-embedded transverse sections.
Axons with thin myelin sheaths can arise for two reasons:

As a consequence of segmental demyelination
As a result of axon regeneration.
- Remyelination associated with axon regeneration can't usually be distinguished from remyelination following primary demyelination by the presence of regeneration clusters.

Repeated bouts of demyelination followed by remyelination can lead to onion bulb formation, where the basal lamina of previously myelinating Schwann cells persist as concentric onion-like layers around the axon.

A further type of peripheral demyelination occurs where the Schwann cell is injured but not killed, or where the myelin sheath is locally damaged.
This can result in partial demyelination, which involves loss of myelin at the end fo the internode called the paranodal region.
The exposed axon is remyelinated by a new, thin myelin cheath which 'intercalates' between adjacent internodes.