Pathophysiology of Peripheral Nerve Injury: A Brief Review

Mark G. Burnett, MD; Eric L. Zager, MD


Neurosurg Focus. 2004;16(5) 

In This Article

Nerve Regeneration

In severe injuries nerve regeneration begins only after Wallerian degeneration has run its course, but in mild injuries the regenerative and repair processes begin almost immediately. For first- and second-degree injuries (neurapraxia and axonotmesis), restoration of function is the rule. This occurs early via reversal of conduction block or late via axonal regeneration. Functional recovery is complete in these milder degrees of injury. Both morphological and physiological changes are fully reversible.

In more severe nerve injuries in which endoneurial tubes are disrupted, regenerating axons are no longer confined to their original sheaths. They may meander into surrounding tissue or into inappropriate endoneurial tubes, thus failing to reinnervate their proper end organs. Neurological recovery is compromised, generally to a degree proportional to the severity of the injury.

Functional recovery after nerve injury involves a complex series of steps, each of which may delay or impair the regenerative process. In cases involving any degree of nerve injury, it is useful initially to categorize these regenerative steps anatomically on a gross level. The sequence of regeneration may be divided into anatomical zones: 1) the neuronal cell body; 2) the segment between the cell body and the injury site; 3) the injury site itself; 4) the distal segment between the injury site and the end organ; and 5) the end organ itself. A delay in regeneration or unsuccessful regeneration may be attributed to pathological changes that impede normal reparative processes at one or more of these zones.

The regeneration and repair phase following nerve injury may last for many months. The earliest signs of this phase are visible changes in the cell body that mark the reversal of chromatolysis. The nucleus returns to the cell center and nucleoproteins reorganize into the compact Nissl granules. Postinjury, many subcellular metabolic functions were altered during chromatolysis. Likewise, RNA synthesis was increased and neurotransmitter synthesis decreased. Chromatolysis heralded a fundamental shift in cell function from synaptic transmission to cellular repair. The metabolic machinery was reprogrammed so that the cell would be able to produce the vast amount of protein and lipid needed for axonal regrowth during the regeneration phase.

A complex and incompletely understood interaction occurs between the cell body and the regenerating axon tip. Axoplasm, which serves to regenerate the axon tip, arises from the proximal axon segment and cell body. Both fast and slow components of axoplasmic transport supply materials from the cell body to the sites of axonal regeneration. The rate of increase in protein and lipid synthesis in the cell body influences the rate of advance and the final caliber of the regenerating axon. The human peripheral neuron's capacity to initiate a regenerative response appears to persist for at least 12 months after injury, and a robust response can be elicited even after repeated injuries.

The length of the segment between the regenerating axon tip and the injury site depends on the severity of the original injury and the consequent retrograde degradation. The first signs of axon regrowth in this segment may be seen as early as 24 hours postinjury, or they may be delayed for weeks in more severe injury. The rate of axonal regrowth is determined by changes within the cell body, the activity of the specialized growth cone at the tip of each axon sprout, and the resistance of the injured tissue between cell body and end organ.

There may be multiple axon sprouts within each endoneurial sheath, even in milder injuries, that do not involve destruction of the sheath itself. The fate of these multiple sprouts is not clear even in experimental paradigms. The timing of degenerative and regenerative processes is such that there must be a significant overlap between these in certain segments. For example, in milder injuries in which there is no significant delay in regeneration across the injury site, the growth cone at the advancing axon tip must encounter the debris of Wallerian degeneration in the distal segment. This debris does not appear to impede regeneration, perhaps because the growth cone secretes a protease that can help dissolve material blocking its path.[6]

In very proximal injuries in which there is considerable delay before the advancing axon tip reaches the distal segment, the empty endoneurial tubes distally have decreased in diameter. This factor may be responsible, in part, for a terminal slowing in axonal regrowth. Surgical intervention that interrupts entering nutrient arteries does not appear to impair axonal regeneration, provided that longitudinal arteries within the nerve itself are not disrupted.

In severe nerve injuries that disrupt the endoneurial tubes, nerve fascicles, or trunks, formidable obstacles face the regenerating axons that reach the injury site. There may be a gap between the disrupted nerve ends, allowing regenerating axon sprouts to wander into surrounding tissue. Scarring is inevitably present at the site of severe injury; the extent depends on multiple factors including the timing of the arrival of the regenerating sprouts after injury.

It has been well documented that regenerating axons may at times successfully traverse long gaps spontaneously, despite the presence of substantial scar tissue; however, there is no question that appropriate surgical repair can eliminate the gap and reduce the amount of intervening scar tissue. This procedure provides no guarantee of proper fascicle orientation, of course, and regenerating axons may grow into functionally inappropriate endoneurial tubes or even may fail to reenter an endoneurial tube. Either circumstance results in wasted axons.

Previously nonmyelinated axons may regenerate into endoneurial sheaths that formerly contained myelinated axons (and vice versa). This regeneration will not be wasteful. The resistance that an axon meets at the injury site results in the formation of multiple smaller axon sprouts. These daughter axons do not all make their way into the distal segment. No specific neurotropism is known to enhance the growth of a regenerating axon into its original endoneurial tube, but some form of neurotropic influence has been demonstrated in experimental paradigms. Scarring within the bridging tissue impedes the regeneration and misdirects axon sprouts in to functionally unrelated endoneurial tubes. Residual scar tissue also interferes with the maturational processes of axons that do negotiate the injury site.

Axons that successfully enter the endoneurial tubes in the segment distal to the injury site stand a good chance of reaching the end organ, given reasonable growth conditions. The distal regeneration rate is slower if the endoneurial tubes have been disrupted because axon sprouts must first find their way into the tubes before advancing. The specialized growth cone at the tip of each axon sprout contains multiple filopodia that adhere to the basal lamina of the Schwann cell and use it as a guide. Both contact and chemotactic guidance have been shown to be important in directing advancement of the growth cone.[3,4] At times, because several small axon sprouts may enter the same endoneurial tube, a regenerated nerve fiber may contain more axons than the original nerve.

If a functionally unrelated end organ is reached, further development of the axon and remyelination do not occur. Similarly, axonal development and maturation are aborted if the end organ, due to prolonged denervation, has undergone degenerative changes that do not allow the establishment of functional connections. If the entry of regenerating axons into the distal segment is delayed more than approximately 4 months, the axons are entering endoneurial tubes of smaller diameter, generally 3 µm or less. This shrinkage may make it more difficult for axon sprouts to locate and enter endoneurial tubes, but this does not appear to impede axonal regrowth once sprouts are inside the tubes. This is presumably due to the elastic properties of the endoneurium.

The return of function does not require absolutely faithful recovery of nerve architecture. The effects of prolonged denervation, which do appear to impair functional recovery, are at the level of the injury site—that is, preventing the regenerating axons from entering appropriate endoneurial tubes—or at the end organ.

End organ undergoes characteristic histological changes with nerve degeneration and subsequent reinnervation. Muscle fibers atrophy quite rapidly (a mean 70% reduction of cross-sectional area by 2 months) and cell nuclei assume a central rather than the normal peripheral position. The synaptic folds of motor endplates are preserved for at least 1 year after denervation.

Tremendous proliferation of fibroblasts also characterizes the histological picture of denervation. New collagen is deposited in both the endo- and perimysium. In general, muscle fibers are not replaced by connective tissue but rather atrophied fibers are separated by thickened connective tissue, so that the overall internal pattern of muscle architecture is preserved. Occasional dropout of muscle fibers does occur. This is a relatively late phenomenon, generally observed between 6 and 12 months after denervation.

Regenerating axonal sprouts follow the original Schwann cells to the denervated motor endplates to reform neuromuscular junctions.[14] Collateral sprouting also occurs, resulting in groups of reinnervated muscle fibers, all of the same fast or slow types. This is a characteristic finding in reinnervated muscle, contrasting sharply with the random pattern observed in normal muscle.

Unfortunately, incomplete motor recovery occurs commonly after moderate-to-severe nerve injuries. This is due to a number of factors within the muscle itself and in the regenerating nerve. Intramuscular fibrosis may limit the efficacy of the contraction produced by a nerve impulse. Appropriate physical therapy can help maintain the denervated muscles in an optimal condition to receive the regenerating axon terminals.

Functional motor recovery is obviously impaired if significant numbers of axons do not successfully reform functional connections with the muscle. Even if the numbers are adequate, erroneous cross-reinnervation may produce a suboptimal functional result: an originally "fast" muscle may be reinnervated by axons previously innervating "slow" muscle, and the result may be a mixed form with inefficient contraction.

In cases in which significant motor recovery occurs, functional outcome may be impaired by concomitant sensory deficits, particularly in proprioception. Denervated sensory receptors survive and may make useful functional recoveries after 1 year and possibly after many years. In first- and second-degree injuries, return of sensation is complete in its original pattern, even after 6 to 12 months of denervation. This is due to faithful reinnervation of sensory receptors by their original axons.

After more severe injuries and nerve repair, sensory recovery is never complete. This is undoubtedly related to a combination of factors, including failure of sensory axons to reach the skin, cross-reinnervation (an axon originally from one type of receptor making connections with a different type of receptor), and possibly degeneration of sensory receptors. Sensory reinnervation appears to be modality specific, but it is less so than motor reinnervation, which means that sensory cross-reinnervation is unfortunately more common. Some controversy exists over the fate of denervated encapsulated sensory receptors. These receptors include Pacinian corpuscles and Meissner corpuscles, which are rapidly adapting receptors mediating light touch and vibration, as well as Merkel cells, which are slowly adapting receptors that mediate constant touch and pressure. It is believed that these specialized receptors survive in an atrophied state for prolonged periods, awaiting the arrival of an appropriate nerve terminal. The survival period has not been clearly established, however, and there is some evidence indicating that the protective sensation, which recovers years after denervation, is mediated by less elaborate sensory receptors.

The rate of axonal regeneration has been assumed to be constant and, in clinical situations, is generally estimated to be 1 mm per day and is often followed by an advancing Tinel sign. Reported rates of regeneration, however, vary broadly from 0.5 to 9 mm per day. This variability is due to several factors. 1) The rate of axon growth decreases with increasing distance from the cell body to the advancing axon tip. 2) Measurements of axonal regeneration were made in different species after different methods of nerve injury. 3) The techniques for measuring regeneration were different (for example, Tinel sign compared with functional recovery). Moreover, the rate of regeneration can depend on the nature and severity of the nerve injury, the duration of denervation, and the condition of the peripheral tissues. Regeneration after surgical nerve repair is slower than uncomplicated regeneration, most likely reflecting the severity of the original injury. Aging has also been shown to retard the rate of axonal regrowth.

Axonal regeneration is not synonymous with return of function. A process of maturation precedes functional recovery. Morphological changes of maturation proceed along the regenerating axon at a slower rate than axon regrowth and continue for a protracted period—as long as 1 year. Remyelination develops in a manner similar to that for developing nerve fibers, involving alignment of Schwann cells and encircling of the axon to form a multilamellated sheath. This process begins within 2 weeks of the onset of axonal regeneration and results in myelinated axons quite similar to the originals except with shortened internodes. The axon's diameter increases progressively until normal dimensions are reached, but this enlargement is dependent on the establishment of functional connections between the axon tip and the appropriate end organ.