Wallerian Degeneration

Wallerian Degeneration
from the textbook
Surgery of the Peripheral Nerve
by Susan E. Mackinnon, A. Lee Dellon

In 1850, Waller described changes in the distal nerve of the glossopharyngeal and hypoglossal nerves of the frog after nerve transection; these changes are now called Wallerian degeneration. The identical changes occur in the proximal segment of the nerve after nerve injury and occur for a varying distance along the proximal portion of the nerve. The distance will vary directly with the severity of the injury and may extend far more proximally than one node of Ranvier. Some lesions will result in death of the cell body. This degeneration pattern appears histologically to be that seen with Wallerian degeneration but is termed “traumatic degeneration.
Site of Nerve Injury
At the level of the nerve injury, the axons will sprout into regenerating units as early as the first 24 hours after injury. A single axon will produce multiple axon limited by the perineurium. This regenerating unit appears to be the minimum functional unit for regeneration. Initially, the regenerating units contain only unmyelinated fibers even when the parent axon is a myelinated fiber. With time, these unmyelinated fibers become myelinated and then, as time progresses, the number of nerve fibers within each regenerating unit probably relates to whether or not the axon has made successful contact with a distal end organ.When these regenerating units reach the distal nerve and appropriate distal receptors, functional recovery may be realized. If the regenerating units are lost in the extraperineurial environment, then a neuroma will be formed. This neuroma will represent potential lost function and may well be a source of neuromatous type pain.In the distal portion of each axon sprout there is a growth cone that consists of filopodia rich in actin. The tips of these filopodia will explore the distal environment and retract back into the body of the growth cone if they make no contact with a physical substrate. By contrast, if they contact a substrate to which they can adhere, they will attach to this structure and draw the entire growth cone distally toward this attachment site. Letourneau has presented videos of growth cones that show these filopodia reaching out into an empty space making no contact, pulling back, and advancing again toward a more appropriate substrate. This process of contact guidance advances the entire growth cone advanced along a grid of laminin. Letourneau has demonstrated that these growth cones prefer to advance along such substances as fibronectin and laminin, which are components of the basil lamina of the Schwann cell. Thus, axons will not grow into an environment that does not have some solid structures within the environment onto which the filopodia of the growth cone can attach. It would appear that the more “adhesive” the substrate is, the greater will be the number of axons that will arise from each single nerve fiber.
Conceptualization of the changes that occur after nerve division.
The primary unit of the peripheral nerve is the nerve fiber. The segmental extrinsic blood supply and the mesoneurium are emphasized. In the extreme lower right, a single nerve fiber is shown protruding from the nerve fascicle. Plexus formation between these two fascicles is seen.
A cut-away view of a single nerve fiber. Note the swelling of the axon on either side of the node of Ranvier. Axon:yellow ;myelin:blue; basal lamina: orange.
After division of the same single nerve fiber, Wallerian degeneration occurs distal to the division. Degeneration will also occur for a variable distance proximal to the nerve division.
Although Wallerian degeneration continues distally in the nerve fiber, an attempt at regeneration occurs proximally. The single nerve fiber will “sprout” to form a regenerating unit. At the tip of each sprout is a growth cone with multiple filopodia. These filopodia will adhere to the basal lamina of the Schwann cell. The Schwann cells are intimately associated with the regenerating fibers. Schwann cells: blue; fibroblast: green; regenerating sprouts: yellow; basal lamina: orange.
As the regenerating unit matures, the individual sprouts become myelinated. Regeneration occurs along the basal lamina of the Schwann cells.
The “parent” single nerve fiber is noted proximally and a cut-away of the mature regenerating unit that has “sprouted” from that single fiber is seen to contain well-myelinated fibers. Basal lamina adjacent to this regenerating unit represents an area of degeneration without regeneration. (Bands of Bungner.)
It is not known how many of the fibers in each regenerating unit will potentially reinnervate distal targets and how may will deteriorate. It is not known whether the potential for maturation of nerve fibers varies in the sensory and motor systems. It is known that early on in the regeneration period, the number of nerve fibers, either in the nerve graft or in the distal nerve across the simple nerve repair, is much higher than in the parent nerve. This is explained by the concept of sprouting and regenerating units, as already discussed. The previous perception that there was an actual loss of nerve fibers across a nerve repair is inaccurate. Although there is certainly loss of regenerating units at the site of the repair in the extraperineurial environment because of the dramatic increase in the total nerve fibers due to the sprouting effect, there is actually an overall increased in nerve fibers that cross the repair. Similarly, if the number of nerve fibers are counted across a simple nerve repair, initially, an increased number of fibers are noted in the distal nerve but with time and the passage of many months, the number of nerve fibers returns to normal. This would be explained by the process of sprouting and distal target contact with maturation of nerve fibers that make distal contact and deterioration of others that do not.
Distal Nerve Segment
After nerve transection, the nerve distal to the transection undergoes Wallerian degeneration. After nerve division, Schwann cells proliferate, the myelin breaks down, and the myelin debris is phagocytosed by the Schwann cells. It may take 1 to 3 months for the Schwann cells to phagocytose all cellular debris completely. Endoneurial tubes, (the basal lamina of the Schwann cells), now collapse because of the phagocytosis of the myelin and axonal components inside these tubes. These endoneurial tubes are now seen as stacked processes of the Schwann cell and have been called “Bands of Bungner.” The proliferating Schwann cells organize themselves into columns. As the axon sprouts from the proximal stump regenerate into the environment of the distal nerve, they associate themselves with these Schwann cells and regenerate between the layers of basal lamina of the Schwann cell processes. These endoneurial tubes should be considered potential tubes rather than thought of as actual empty tubes into which the nerve sprouts will grow. If the regenerating sprouts enter or travel along inappropriate tubes (for example, sensory and motor) there will be misdirection of growth, and the final functional result will not be good. The final result will depend on the number of axon sprouts that associate themselves with the appropriate Schwann cell columns and reinnervate appropriate end organs. Bands of Bungner in the distal nerve segment represent these potential endoneurial tubes that have not been re-innervated. After nerve repair, Wallerian degeneration will occur in the distal nerve. This process will last several weeks. Fiber regeneration from the proximal stump across the repair will occur within several hours to days of the injury. In the distal nerve these two processes must be thought of as occurring concurrently. The axonal sprouts will regenerate down the distal segment at rates varying between 1 and 4 mm per day.

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Ray Jurewicz
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