nerve injury nerve injury nerve injury is an injury to nervous tissue. there is no single classification system that can describe all the many variations of nerve injuries. in 1941, seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve. usually, however, peripheral nerve injuries are classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved. nerve injurymicrograph of a nerve with a decrease in myelinated nerve fibres (pink) and an abnormal increase in fibrous tissue (yellow), as may be seen in nerve injuries. hps stain.specialtyneurology unlike in the central nervous system, neuroregeneration in the peripheral nervous system is possible. the processes that occur in peripheral regeneration can be divided into the following major events: wallerian degeneration, axon regeneration/growth, and reinnervation of nervous tissue. the events that occur in peripheral regeneration occur with respect to the axis of the nerve injury. the proximal stump refers to the end of the injured neuron that is still attached to the neuron cell body; it is the part that regenerates. the distal stump refers to the end of the injured neuron that is still attached to the end of the axon; it is the part of the neuron that will degenerate, but the stump remains capable of regenerating its axons. the study of peripheral nerve injury began during the american civil war and greatly expanded during modern medicine with such advances as use of growth-promoting molecules. types to assess the location and severity of a peripheral nerve injury, clinical assessment is commonly combined with electrodiagnostic tests. injuries to the myelin are usually the least severe (neuropraxia), while injuries to the axons and supporting structures are more severe (axonotmesis is moderate injury, while neurotmesis is severe injury). it may be difficult to differentiate the severity by clinical findings due to common neurological impairments, including motor and sensory impairments distal to the lesion. neurapraxia nerve compression in neurapraxia neurapraxia is the least severe form of nerve injury, with complete recovery. in this case, the axon remains intact, but there is myelin damage causing an interruption in conduction of the impulse down the nerve fiber. most commonly, this involves compression of the nerve or disruption to the blood supply (ischemia). there is a temporary loss of function which is reversible within hours to months of the injury (the average is 6–8 weeks). wallerian degeneration does not occur, so recovery does not involve actual regeneration. there is frequently greater involvement of motor than sensory function with autonomic function being retained. in electrodiagnostic testing with nerve conduction studies, there is a normal compound motor action potential amplitude distal to the lesion at day 10, and this indicates a diagnosis of mild neurapraxia instead of axonotmesis or neurotmesis. axonotmesis this is a more severe nerve injury with disruption of the neuronal axon, but with maintenance of the epineurium. this type of nerve damage may cause paralysis of the motor, sensory, and autonomic, and is mainly seen in crush injury. if the force creating the nerve damage is removed in a timely fashion, the axon may regenerate, leading to recovery. electrically, the nerve shows rapid and complete degeneration, with loss of voluntary motor units. regeneration of the motor end plates will occur, as long as the endoneural tubules are intact. axonotmesis involves the interruption of the axon and its covering of myelin, but with preservation of the connective tissue framework of the nerve (the encapsulating tissue, the epineurium and perineurium, are preserved). because axonal continuity is lost, wallerian degeneration occurs. electromyography (emg) performed 2 to 4 weeks later shows fibrillations and denervation potentials in musculature distal to the injury site. loss in both motor and sensory spines is more complete with axonotmesis than with neurapraxia, and recovery occurs only through regenerations of the axons, a process requiring time. axonotmesis is usually the result of a more severe crush or contusion than neurapraxia, but can also occur when the nerve is stretched (without damage to the epineurium). there is usually an element of retrograde proximal degeneration of the axon, and for regeneration to occur, this loss must first be overcome. the regeneration fibers must cross the injury site and regeneration through the proximal or retrograde area of degeneration may require several weeks. then the neuritis tip progresses down the distal site, such as the wrist or hand. proximal lesion may grow distally as fast as 2 to 3 mm per day and distal lesion as slowly as 1.5 mm per day. regeneration occurs over weeks to years. neurotmesis neurotmesis is the most severe lesion with no potential of full recovery. it occurs on severe contusion, stretch, or laceration. the axon and encapsulating connective tissue lose their continuity. the last (extreme) degree of neurotmesis is transsection, but most neurotmetic injuries do not produce gross loss of continuity of the nerve but rather internal disruption of nerve structures sufficient to involve perineurium and endoneurium as well as axons and their covering. denervation changes recorded by emg are the same as those seen with axonotmetic injury. there is a complete loss of motor, sensory and autonomic function. if the nerve has been completely divided, axonal regeneration causes a neuroma to form in the proximal stump. for neurotmesis, it is better to use a new more complete classification called the sunderland system. overview of peripheral regeneration wallerian degeneration is a process that occurs before nerve regeneration and can be described as a cleaning or clearing process that essentially prepares the distal stump for reinnervation. schwann cells are glial cells in the peripheral nervous system that support neurons by forming myelin that encases nerves. during wallerian degeneration schwann cells and macrophages interact to remove debris, specifically myelin and the damaged axon, from the distal injury site. calcium has a role in the degeneration of the damage axon. bands of büngner are formed when uninnervated schwann cells proliferate and the remaining connective tissue basement membrane forms endoneurial tubes. bands of büngner are important for guiding the regrowing axon. at the neuronal cell body, a process called chromatolysis occurs in which the nucleus migrates to the periphery of the cell body and the endoplasmic reticulum breaks up and disperses. nerve damage causes the metabolic function of the cell to change from that of producing molecules for synaptic transmission to that of producing molecules for growth and repair. these factors include gap-43, tubulin and actin. chromatolysis is reversed when the cell is prepared for axon regeneration. axon regeneration is characterized by the formation of a growth cone, which has the ability to produce a protease that digests any material or debris that remains in its path of regeneration toward the distal site. the growth cone responds to molecules produced by schwann cells such as laminin and fibronectin. neuron-intrinsic changes immediately following injury, neurons undergo a large number of transcriptional and proteomic changes which switch the cell from a mature, synaptically active neuron to a synaptically silent, growth state. this process is dependent on new transcription, as blocking the ability of cells to transcribe new mrna severely impairs regeneration. a number of signaling pathways have been shown to be turned on by axon injury and help to enable long distance regeneration including bmp, tgfβ, and mapks. similarly, a growing number of transcription factors also boost the regenerative capacity of peripheral neurons including ascl1, atf3, creb1, hif1α, jun, klf6, klf7, myc, smad1, smad2, smad3, sox11, srf, stat3, tp53, and xbp1. several of these can also boost the regenerative capacity of cns neurons, making them potential therapeutic targets for treating spinal cord injury and stroke. role of schwann cells guillain–barré syndrome – nerve damage schwann cells are active in wallerian degeneration. they not only have a role in phagocytosis of myelin, but they also have a role in recruitment of macrophages to continue the phagocytosis of myelin. the phagocytic role of schwann cells has been investigated by studying the expression of molecules in schwann cells that are typically specific to inflammatory macrophages. expression of one such molecule mac-2, a galactose-specific lectin, is observed in not only degenerating nerves that are macrophage-rich but also degenerating nerves that are macrophage-scarce and schwann cell-rich. furthermore, the effects of mac-2 in degenerating nerves are associated with myelin phagocytosis. there was a positive correlation between the amount of mac-2 expression and the extent of myelin phagocytosis. a deficiency in mac-2 expression can even cause inhibition of myelin removal from injury sites. schwann cells are active in demyelination of injured nerves before macrophages are even present at the site of nerve injury. electron microscopy and immunohistochemical staining analysis of teased nerve fibers shows that before macrophages arrive at the injury site, myelin is fragmented and myelin debris and lipid droplets are found in the cytoplasm of schwann cells, indicating phagocytic activity before macrophages arrive. schwann cell activity includes recruitment of macrophages to the injury site. monocyte chemoattractant protein (mcp-1) plays a role in recruiting monocytes/macrophages. in tellurium-induced demylenation with no axon degeneration, nerve crush with axon degeneration, and nerve transection with axon degeneration an increase in mcp-1 mrna expression followed by an increase in macrophage recruitment occurred. in addition varying levels of mcp-1 mrna expression also had an effect. increased mcp-1 mrna levels correlated positively with an increase in macrophage recruitment. furthermore, in situ hybridation determined that the cellular source of mcp-1 was schwann cells. schwann cells play an important role in not only producing neurotrophic factors such as nerve growth factor (ngf) and ciliary neurotrophic factor (cntf), which promote growth, of both the damaged nerve and supporting schwann cells, but also producing neurite promoting factors, which guide the growing axon, both of which are discussed below. role of macrophages the primary role of macrophages in peripheral regeneration is demylenation during wallerian degeneration. immunohistochemical analysis showed that in tellurium demylenated, crushed, and cut nerves, expression of lysozyme, which is a marker for myelin phagocytosis, and of ed1, which is a marker for macrophages, occurred in the same region. lysozyme was also investigated with respect to the temporal progression of myelin phagocytosis by macrophages in nerve injury. northern blotting showed that peak lysozyme mrna expression occurred at an appropriate time with respect to temporal models of myelin phagocytosis. macrophages do not phagocytose all cellular debris at the nerve injury site; they are selective and will salvage certain factors. macrophages produce apolipoprotein e which is involved in rescuing cholesterol in damaged nerves. in the same investigation, temporal levels of apolipoprotein e mrna expression in the three models for demylenation and nerve damage were consistent with respect to models for cholesterol salvage in nerve injury. macrophages play a role in salvaging cholesterol during nerve injury. macrophages also play a role in inducing the proliferation of schwann cells that occurs during wallerian degeneration. supernatant has been collected from medium in which macrophages are active in myelin phagocytosis where lysosomal processing of the myelin occurs within the macrophage. the supernatant contains a mitogenic factor, a mitosis promoting factor, that is characterized heat and trypsin sensitivity, both of which characterize it as a peptide. treatment of schwann cells with the collected supernatant shows that it is a mitogenic factor and thus plays an important role in the proliferation of schwann cells. macrophages are also involved in the secretion factors that promote nerve regeneration. macrophages secrete not only interleukin-1, a cytokine that induces expression of nerve growth factor (ngf) in schwann cells but also an interleukin-1 receptor antagonist (il-1ra). expression of il-1ra in mice with transected sciatic nerves via implantation of a tube releasing il-1ra showed the regrowth of fewer myelinated and unmyelinated axons. macrophage secretion of interleukin-1 is involved in stimulation of nerve regeneration. role of neurotrophic factors several signaling pathways are upregulated following a nerve injury. neurotrophic factors are those that promote survival and growth of neurons. a trophic factor can be described as a factor that is associated with providing nourishment to allow for growth. in general they are protein ligands for tyrosine kinase receptors; binding to the specific receptor yields autophosphorylation and subsequent phosphorylation of tyrosine residues on proteins that participate in further downstream signaling to activate proteins and genes involved in growth and proliferation. neurotrophic factors act through