Peripheral Nerve Injury

Transcription

1 Advances in Physiotherapy 2003; 5:67 82 Peripheral Nerve Injury MERRILL LANDERS, DPT, OCS, and PETER ALTENBURGER, MSPT College of Health Sciences, Department of Physical Therapy, University of Nevada, Las Vegas, 4505 Maryland Parkway, Box , Las Vegas, NV , USA apist. Specifically, this article will cover tionally, the paucity of physiotherapy- Abstract current tends in surgical management generated research devoted to outcomes Management of the patient with a peview and nerve growth enhancement. A re- of these injuries demonstrates the need ripheral nerve injury should be based of research relevant to rehabilita- for continued work in this area. on a sound knowledge of the underly- tion concepts that illustrates the role of ing anatomy, nerve injury classification, physiotherapist in the management of KEY WORDS: nerve degeneration pathophysiology and medical managegeneration nerve injuries and repairs will also be nerve injury classification nerve re- ment. This review of the literature ad- discussed. This role includes post-injury nerve repair peripheral dresses those topics with a depth and rehabilitation, post-operative rehabilitabreadth nerve injury physiotherapy rehabil- appropriate for the physiother- tion and evaluation of recovery. Addinerve itation. INTRODUCTION Patients who have had a peripheral nerve injury often require physiotherapy to improve their function. This is particularly true for patients who have had a cumulative trauma disorder, e.g. carpal tunnel, in which peripheral nerve function has been comprised. This type of injury is well documented in the physiotherapy literature and thoroughly covered in most physiotherapy educational programs. Less commonly addressed in the physiotherapy literature and educational programs are the peripheral nerve injuries that are caused by compression, crush, stretch and laceration. Historically, physiotherapists have treated the consequences of these traumatic nerve injuries; however, modern, orthopedic-oriented physiotherapists, much like their professional education, have devoted little time to the subject. In fact, there is a paucity of research devoted to peripheral nerve injury in the physiotherapy literature. A literature review, conducted by the authors, found only ancillary articles devoted to this subject. It has been estimated that there are approximately 19,500 new cases of traumatic peripheral nerve injuries each year in the USA alone (1). These types of specific peripheral nerve injuries can result in significant loss of function and require extensive surgical intervention. The patient s resulting deficits will involve considerable physiotherapy intervention to gain functional recovery. Due to the traumatic nature of these injuries, they seldom occur in isolation and are often accompanied by significant musculoskeletal injury. Therefore, physiotherapy intervention should focus on all involved tissue without neglecting injury to the peripheral nervous system. Gaining an understanding of the underlying neural anatomy, pathophysiology and medical management of peripheral nerve injuries will enable the therapist to make informed clinical decisions, based on current knowledge. This is a detailed review of the literature with the intent to increase the reader s foundational knowledge of the pathophysiology and clinical presentation of peripheral nerve injuries. In addition, an update of the latest surgical interventions associated with significant nerve injury will be provided. Finally, some rehabilitative concepts specific to nerve regeneration will be discussed. The articles that were included in this review were all found using a MEDLINE search engine and were selected based on current trends in medical management and relevance to physiotherapy. NERVE ANATOMY AND PHYSIOLOGY The peripheral nerve consists of sensory, motor and autonomic nerve fibers. All peripheral nerve fibers 2003 TAYLOR & FRANCIS ISSN DOI: /

2 M. LANDERS & P. ALTENBURGER Advances in Physiotherapy 5 (2003) are incased in supportive Schwann cells. Individual unmyelinated and myelinated nerve fibers are surrounded by a connective tissue called the endoneurium (Fig. 1). The endoneurium is contiguous with the pia mater in the central nervous system. This supportive connective tissue forms endoneurial tubes around each axon and associated Schwann cells. It is collageneous with no elastin and minimal fibroblasts (2) and serves to resist elongation. Groups of endoneurial-encased fibers run the length of a nerve and are called fascicles. The number of fascicles within a given nerve may vary from one individual to the next. These fascicles do not run as structured parallel cables, but rather form interfascicular connections or plexi throughout the length of the nerve. Fascicle orientation varies significantly over the length of a nerve and can be considerably different over a span of a few millimeters. Each fascicle is surrounded by a thin, multilayered, dense connective tissue sheath called the perineurium. A fascicle, therefore, is a group of nerve axons packed within endoneurial tubes and encased in perineurium. Perineurium is a very strong layer and serves to protect the fascicle from longitudinal stretch. It is contiguous with the arachnoid mater of the central nervous system. Groups of fascicles are bound together by a yet another connective tissue called epineurium. It is divided into two different layers, a loose connective tissue composed of collagen fibers, which fills the space between fascicles (internal epineurium), and a dense layer of connective tissue surrounding the entire nerve (external epineurium). The internal epineurium acts as a cushion from external pressure and facilitates longitudinal motion between fascicles. The external epineurium holds all of the fascicles together and maintains structural integrity of the nerve. The epineurium comprises 25 75% of a nerve s cross sectional area (3,4). Fibrosis of such structures, as is common with chronic nerve compression, may inhibit longitudinal gliding between fascicles (3). Also, in the proximal limb regions and over joint areas, the nerve epineurium is more developed. Chronic nerve compression and surgical Fig. 1. Anatomy of a peripheral nerve. Subset pictures A (unmyelinated) and B (myelinated) have the outer endoneurial tissue removed. 68

3 Advances in Physiotherapy 5 (2003) PERIPHERAL NERVE INJURY nerve repair may cause the epineurium to thicken and adhere to surrounding tissues (3). These tissue adhesions decrease the nerve s ability to glide and may result in a superimposed traction injury (3). In contrast to the perineurium, removal of the epineurium will result in relatively few physiological side effects (2). A layer of loose areolar tissue continuous with the epineurium helps the nerve to maintain longitudinal excursion. It is called the mesoneurium, and receives segmental or extrinsic blood supply, which enters along the course of the nerve. The nerve also has an intrinsic blood supply originating at the spinal cord, which travels longitudinally within the epineurium, perineurium and endoneurium. The larger vessels are located within the epineurium and perineurium, while the endoneurial supply is mainly from a capillary network. Extensive connections exist between the intrinsic and extrinsic blood supply. It has been shown that vascular supply to the peripheral nerves can be intrinsically dominant, extrinsically dominant or neither (5). Nerves that are intrinsically dominant will have less dysfunction as a result of loss of the extrinsic supply (5). Extensive mobilization and nerve transposition procedures may damage the nerve s extrinsic blood supply, but because the nerve relies more heavily on the intrinsic supply, there is minimal disruption. Blood supply can also be compromised by adverse tension. Lundborg & Rydevik indicate that elongation of approximately 8% of the rabbit tibial nerve is enough tension to cause definite impairment of the intraneurial microvascular flow (6). Moreover, they demonstrated that a 15% elongation will cause total occlusion resulting in complete ischemia (6). Much like the brain, the peripheral nerve is isolated immunologically from the rest of the body. This is called the blood nerve barrier. It is homologous to the blood brain barrier in the central nervous system. This barrier occurs at the endothelial cells of the endoneurium and at the internal layer of perineurium (7). It is only permeable to simple sugars, unless it is violated by injury. Disruption of this barrier as a result of injury could lead to an immunological response directed at components of the peripheral nerve, which may serve to amplify the extent of the primary injury. NERVE INJURY CLASSIFICATION Nerve injuries result from compression, crushing, trauma, laceration, chemical irritation and stretching. The two most widely accepted nerve injury classification systems were developed by Seddon et al. (8) and Sunderland (9). Seddon described three distinct types of nerve injury: neurapraxia, axonotmesis and neurotmesis. Sunderland later proposed an expansion of that classification system. This system lists five types of nerve injuries based on the structures that are damaged: first degree (neurapraxia), second degree (axonotmesis), third degree, fourth degree and fifth degree (neurotmesis) (Table I). The most mild of the nerve injuries is neurapraxia or first-degree Sunderland injury, which is most commonly caused by compression, e.g. nerve entrapment syndromes, carpal tunnel, etc. It is a localized conduction loss at the injury site with normal conduction both proximal and distal to the injury. Nerve continuity is patent and there is no axonal injury. Mild histological changes may occur, including segmental demyelination. Axonotmesis or second-degree Sunderland injury is a localized axonal injury with subsequent Wallerian degeneration distally from the lesion. This type of injury has numerous causes including chronic compression, acute crush and stretch. Disruption to the axon results in axonal sprouting from the viable proximal end. The distal endoneurium, perineurium and Schwann cell envelope remain intact and help to facilitate and direct the proximal axonal sprouts to the target organ. Axonal sprouts will regenerate through the endoneurial tubes at an average rate of 1 2 mm per day (8 10). The rate of regeneration can be monitored with an advancing Tinel sign, which is performed by tapping along the distal nerve (3). Symptom provocation via tapping indicates the location of axonal sprouts and should be repeated weekly to assess progress. After a closed stretch injury, the diagnosis of the type of nerve injury cannot be made until after recovery. If full recovery is observed within the first 3 months of injury, then it is classified as neurapraxia (first-degree Sunderland). If the recovery had advanced at 1 2 mm/day as demonstrated by an advancing Tinel sign, then the injury is classified as axonotmesis (second-degree Sunderland). 69

4 M. LANDERS & P. ALTENBURGER Advances in Physiotherapy 5 (2003) TABLE I: Nerve injury classification Seddon (8), Sunderland MacKinnon Description Anatomic lesion 1943 (9), 1951 (10), 1992 Neurapraxic First degree Localized conduction loss, usually caused by compression No axonal injury Axonotmesis Second degree Axonal injury with Wallerian Axon degeneration Third degree Regeneration limited by scar tissue, Axon, myelin, endoneurium recovery incomplete Fourth degree Epineurium preserved, extensive Axon, myelin, endoneurium scarring, result of stretch or traction, recovery incomplete, surgical intervention warranted perineurium Neurotmesis Fifth degree Most severe of the injuries, complete Axon, myelin, endoneurium transection, surgical intervention perineurium epineurium warranted Sixth degree Difficult to manage Varying levels of damage to all five of the tissues A third-degree Sunderland injury is also an axonotmetic injury with more involvement than a second-degree injury. This type of injury may result from chronic compression, acute crush and stretch. It includes damage to the endoneurium and basal lamina of the Schwann cells. The perineurium remains intact, but the advancing nerve sprouts must make their way through scar tissue caused by the destroyed endoneurium and Schwann cells. This leads to incomplete regeneration and possible mismatching of the regenerating nerve fibers to the appropriate distal receptors. Preservation of the perineurium confines the regrowing nerve sprouts to one fascicle. Functional recovery with this type of injury is incomplete and varies from very minimal to near complete. The regrowing nerve fiber attempts advancement at the same rate (1 2 mm/day) as the second-degree Sunderland injury. However, because the regrowing nerve fibers must make their way through scar tissue, this rate is decreased. A fourth-degree Sunderland injury is also an axonotmetic injury with widespread damage to the Schwann cells, endoneurium and perineurium. The most common etiology of this type of injury is stretch and acute crush. The gross appearance of the nerve is normal secondary to the preservation of the epineurium. However, scarring within the nerve is extensive and inhibits the regrowing nerve fibers from reaching their destination. A Tinel sign will be present, but will not be advancing as it does in the second- and third-degree Sunderland injuries. At 3 months, first-, second- and third-degree Sunderland injuries will have become evident with some signs of recovery. If there is no evidence of recovery by 3 months, then it is considered a fourth-degree injury. Surgical management should therefore be considered. Neurotmesis or fifth-degree Sunderland injury is the most severe of the nerve injuries. It is a complete transection usually associated with an open traumatic injury. Surgical intervention is warranted. A sixth-degree injury has been recently added (11) (Table I). This type of injury is a mixed injury involving all or many of the disrupted tissue associated with Sunderland s fifth-degree classification. Some fascicles or fibers may be first- or second-degree injuries whereas others may be third-, fourthor fifth-degree in nature. Classification and management of these injuries is difficult. These injuries may also be masked by significant musculoskeletal injury. Careful observation by the physiotherapist may help detect an injury that warrants surgical intervention. 70

5 Advances in Physiotherapy 5 (2003) PERIPHERAL NERVE INJURY NERVE PATHOPHYSIOLOGY Following a traumatic nerve injury, many pathophysiological events take place including morphological and metabolic changes. These changes occur in the nerve cell body and within the axon both proximal and distal to the injury site. Changes are also noted in the muscle, sensory receptors and cerebral cortex. Several hours following axonal injury there will be changes within the nerve cell body. The cell body, nucleus and nucleolus all swell in size. This is called chromatolysis. The function of the metabolic machinery in the cell transforms from production of neurotransmitters to the fabrication of axonal structural components needed for repair of the injured axon. This includes increased production of ribonucleic acid, protein components, lipids, glucose-6-phosphate dehydrogenase and hydrolytic enzyme (12,13). Changes can also be noted almost immediately at the site of the injury. Multiple axonal sprouts will begin to emerge from the proximal axon within hours of the injury (2,14,15). The first sprouts will appear from the most distal node of Ranvier within millimeters of the transection (16 18). The distal most end of each of the axonal sprouts is an actin-rich filopodia called the growth cone (19). The terminal Schwann cell also sends out processes, which act as guides for the growing axonal sprouts (20). The rate of nerve regeneration is dependent on these Schwann cell processes (20). Thomas has demonstrated that distal Schwann cells also send back processes to help guide the regrowing axon toward the appropriate endoneurial tube (21). Wallerian degeneration will result following axonotmesis or second-, third- and fourth-degree Sunderland injuries. This process starts immediately after injury and involves primarily the breakdown of Schwann cells distal to the injury. Subsequently, there is a migration and proliferation of Schwann cells and macrophages to the distal axon. Macrophages digest the distal axon and myelin debris (22) and stimulate the proliferation of Schwann cells (23). This phagocytosis occurs along the length of the distal axon resulting in a hollowing out of the endoneurial tube, leaving only the basement membrane of the intact Schwann cells. Complete clearing of this debris may take up to 3 months (2,7). The proliferating Schwann cells align in columns along the length of the nerve and will eventually wrap around the axon to form myelin if the parent cell was myelinated. Neurotrophic and neurotropic changes occur at the injury site as well. Neurotrophism refers to factors that promote growth and maturation of the new axon, whereas neurotropism refers to the influence or guidance of the growing axon toward an appropriate target. Neurotrophic changes at the injury site include an increase in nerve growth factor (NGF) (24 26), ciliary neurotrophic factor (CNF) (24), insulin-like growth factor type 1 (IGF), brainderived neurotrophic factor (BDNF) (25) and neurotrophin-3 and 4 (25). Furthermore, macrophages produce many important cytokines, including interleukin-1 (IL-1) (27) and IGF, both of which are known to promote the growth of axons. IL-1 is known to trigger the production of NGF, which may in some way facilitate the survival and regeneration of the damaged sensory nerve (26). This is also supported by Taniuchi s finding of increased NGF receptor expression on the distal Schwann cells following nerve transection (28). Neurotropic effects are generated from the peripheral nerve stump and denervated muscle. MacKinnon et al. have shown that regenerating nerves will preferentially grow toward distal nerve stumps rather than toward muscle or tendon (29). Researchers have also demonstrated that a proximal peroneal nerve stump will preferentially grow toward its distal end rather than to a posterior tibial nerve stump (30). Furthermore, a nerve will innervate denervated muscle but not innervated muscle (7). Brushart has indicated in a number of studies that motor axons preferentially re-innervate motor targets even if the repair is intentionally malaligned or a gap was imposed between proximal and distal stumps (31 33). If a growth sprout does not receive adequate neurotropic guidance or is unable to find the distal end organ, then it may wander about eventually forming a local neuroma. Most neuromas are asymptomatic, but can become painful and disabling, particularly when irritated by scar tissue 71

6 M. LANDERS & P. ALTENBURGER Advances in Physiotherapy 5 (2003) (34). Neuromas occur most frequently in those who have had a severed nerve as a result of amputation. In addition to neurophysiological changes in the nerve, consequences can also be noted to regions associated with the nervous system. For instance, muscle cells will begin to atrophy following the loss of neural input within 1 week (2). Furthermore, functional muscle re-innervation diminishes if the axon does not reach the motor endplate by 12 months (35). Fu and Gordon suggest that the primary reason for poor functional return is a decrease in the intramuscular nerve pathways, as opposed to the muscle atrophy itself (36). Unlike the motor system, sensory nerves can re-establish functional sensation (two-point discrimination) years after an initial denervation injury. The literature has demonstrated that all types of sensory nerve endings can be re-innervated, including free nerve endings, Pacinian corpuscles, Meissner s corpuscles, Ruffini endings and Merkel cells (2,37). Investigators suggest that functional sensation decreases if the delay in repair has been longer than 6 months (38). It has also been suggested that those with denervation injuries of greater than 1 year in duration can expect only protective sensation return with minimal two-point discrimatory ability (2). Following sensory nerve injury, there is a decrease in the excitatory neuropeptides substance P and calcitonin gene-related peptide as well as an increase in the inhibitory neuropeptides tyrosine and galanin (39). This reduces transmission in the dorsal horn, which would adaptively limit the consequences of peripheral nerve damage to the organism as a whole and to promote survival and recovery of the individual neuron (39). Peripheral nerve injury also has important consequences for the sensory and motor cortices of the central nervous system. The somatosensory cortex undergoes reorganization in response to axonal injury, nerve repair and re-innervation (40 42). Peripheral regeneration has also been shown to result in a reactivation of cortical circuits, which indicate that cortical neurons recover their capacity to process sensory input (42). Sanes et al. demonstrated functional reorganization of the primary motor cortex occurs in response to nerve transection (43). SURGICAL REPAIR Surgery is indicated in Sunderland fourth-degree, fifth-degree and sixth-degree injuries. Primary operative nerve repair occurs within the first week after injury, while secondary repair occurs after 1 week. Secondary procedures are generally indicated when there is infection or when debridement is needed. Ducker et al. advocate a delay of 2 3 weeks to allow surgery to coincide with regenerative metabolic activity (12). Although the previous study is theoretically compelling, primary repair has been shown to be superior to secondary repair in several animal (44 46) and clinical studies (47 49). Current surgical techniques are of two basic types, epineurial and fascicular. Both are microscopic assisted techniques, which have shown favorable results. Some studies have demonstrated no superiority between techniques (50,51), while others support epineurial repair (52,53) and fascicular repair (54). The epineurial procedure is performed by aligning the fascicles and suturing the epineurial sheath, whereas fascicular procedure involves microscopic alignment of the fascicles and then suturing the perineurium to maintain continuity. Aligning these fascicles is technically difficult and can be done in the following ways: size and shape of fascicles, alignment of longitudinal vessels in the epineurium, electrical mapping and histochemical staining. Theoretically, fascicular repair appears to be the more precise method, but presently there is no empirical evidence to suggest its superiority over epineurial repair. Mismatching and increased manipulation of the nerve during the surgery are two possible reasons why fascicular repair has not been shown to be superior (53). Although less exact, epineurial repair may allow guiding neurotropic effects to align appropriate proximal and distal fascicles and is considered the gold standard (34). Conventional suturing is used for either technique. Fibrin glue and laser neurorrhaphy have also been used to adhere the approximated nerve ends, but studies indicate their inferiority to the conventional suture technique (55). Occasionally, nerve grafting is required when endto-end suturing is not possible. This usually occurs when there has been a segmental loss of the nerve due to trauma or when there has been a retraction of 72

7 Advances in Physiotherapy 5 (2003) PERIPHERAL NERVE INJURY the nerve fibers following a delay in repair. Whenever a tension free repair is not possible, then nerve grafting should be performed. A nerve graft with two suture lines is better than a primary repair with one suture line under tension. Abnormal tension will decrease intrinsic blood flow. Clark et al. have shown that an 8% elongation of the nerve will result in a transient 46% decrease in perfusion (56). An increase in tension may also promote scar tissue formation and adhesion at the repair site (2,57,58). Terzis et al. demonstrated a decrease in conduction velocity with repair under severe stretch (58). Nerve transposition is another surgical procedure used to gain a few centimeters and, thus, decrease tension. The most optimal technique of nerve grafting is the autogenous graft which is a nerve harvested from another region within the injured person s body (59). The most frequently used donor sites are the sural, lateral antebrachial cutaneous and the anterior branch of the medial antebrachial cutaneous nerves. Regeneration through grafts is usually less successful than primary repair because of differences in nerve diameter, fascicular variation and fiber size. In addition, graft material does not provide the tropic and trophic factors that aid in nerve regeneration. An alternative to the autogenous graft is the allograft transplantation, which is a graft taken from an intraspecies donor. In separate studies, MacKinnon et al. demonstrated functional sensory re-innervation of the sciatic nerve using multiple cable allografts spanning cm gaps (10,60). Allografts are generally treated with high-dose irradiation or freezedrying to decrease the immunological response. Unlike other transplants, nerve allografts do not need long-term immunosuppression because the graft is acting only as a temporary scaffolding for the regenerating nerve (10). Xenograft transplantation, which is a graft taken from another species, has also been investigated; however, poor and unpredictable outcomes have resulted in little interest (61,62). Use of conduits to bridge the proximal stump with the distal stump is becoming a favorable alternative to the allograft. A wide variety of bioabsorbable and non-bioabsorbable substances have been used, including arteries, veins, tendon and synthetic substances. Two studies have shown good nerve regeneration through venous conduits (63 65). Satifactory nerve regeneration has also been demonstrated utilizing biodegradable collagenous grafts (66), muscle grafts (67 70), epineurial sheaths (71) and omental wrapping (72). Synthetic conduits, i.e. silicone (73,74), glycolide trimethylene carbonate (75) and bioabsorbable polyglycolic acid (PGA) (38,76,77), have also shown promising results. Lundborg et al. demonstrated regeneration across a 10-cm gap using silicone tubing (78). Kiyotani et al. reported good nerve regeneration across a 25-mm gap in cat sciatic nerve using a bioabsorbable polyglycolic acid-collagen tube (77). Dellon & MacKinnon demonstrated nerve regeneration across a 3-cm gap through a bioabsorbable polyglycolic acid conduit in a primate model (76). Despite good experimental success, synthetic grafts have been known to cause chronic irritation, inflammation and nerve compression (79). Furthermore, there has been reported cases of extrusion from the repair site, folding of a simirigid tube, neuroma formation and persistent pain because of entrapment neuropathies as a result of synthetic conduits fashioned from non-absorbable silicone-polymer (79). In short, nerve grafting plays an important role in nerve repair primarily when a tension free repair is not possible. Moreover, the effectiveness of synthetic grafts, particularly for short distances, will help to avoid donor site morbidity. Primary repair is optimal. However, when it is not feasible, then graft transplantation becomes a favorable alternative. Another procedure that has been used in major brachial plexus injuries to restore function is neurotization. This technique involves transferring a less important sensory or motor nerve to a more critical motor or sensory territory. In complete root avulsion of the brachial plexus, intercostal nerves can be transferred to the musculocutaneous nerve either directly or with a nerve grafting procedure to restore biceps function (9,80). Another important consideration in the surgical management of nerve injury is the timing of the repair. The type of injury, open or closed, will dictate this timing. If the injury is closed, then it is better to wait until the full extent of the injury manifests. This may take up to 3 months. If it is an open wound and the two ends are clean and can be approximated, then repair should be performed within the first few 73

8 M. LANDERS & P. ALTENBURGER Advances in Physiotherapy 5 (2003) days. If the wound is open with damage over a long portion of the nerve, then postponing surgery until the full extent of the injury is appropriate. This may take 3 4 weeks. ENHANCEMENT OF NERVE REGENERATION Factors known to facilitate and/or increase the quality of nerve repair are also being investigated. Currently under investigation are NGF (24,26,81), IGF (82), BDNF (83), fibroblast growth factor (FGF) (82,84), ciliary neurotrophic factor (CNF) (81) and the glycoprotein laminin (24,82,85). NGF has been shown to significantly increase the quantity of nerve processes in motor neurons (86). One study reported increased myelination, thicker myelin sheaths, and more mature endoneurial layers when NGF was injected into a silicone reservoir of a repaired peripheral nerve (87). A similar study demonstrated enhanced nerve regeneration through a silicone chamber with local application of NGF (88). NGF has also been shown to slow the rate of neuronal death (89). These studies demonstrate the potential of NGF to augment the outcomes of surgical repair. Other factors applied locally or systemically have also been shown to enhance nerve regeneration. Successful local factors include alpha-melanocyte stimulating hormone (90), collagen and laminin gels (91), and cyclosporin A (92 94). Systemic administration of IGF causes a significant improvement of nerve regeneration following a crush injury (95). FGF is one factor that has been shown to be beneficial both locally and systemically (84). In addition to chemical enhancement, electrical modalities have also been used by physiotherapists to potentiate nerve regeneration. Types of electrical stimulation that have shown enhanced regeneration include direct current electrical fields (90,96 100), pulsed monophasic current applied to the muscle (101), pulsed monophasic current applied to the proximal nerve (102), electrically polarized conduits (103) and biphasic pulsed current directly applied to the regenerating nerve (104). Stimulation is thought to affect calcium channels and either associated membrane potentials or the charged surface membrane molecules at the growth cone (97). Others speculate that electrical stimulation may incite the release of both tropic and trophic factors (7). Multiple studies using animal models have evaluated the effect of applying electrical stimulation to the proximal axon. These authors have used both monophasic (102) and biphasic pulsed current (105), and have demonstrated increased growth rates when compared to control groups (96). Additional investigations have considered stimulation of the distal axon following injury. Similarly, these studies have demonstrated significant enhancement of nerve growth in treatment groups (99,106,107). Other sights for electrical stimulation have been investigated to determine their impact on nerve regeneration. Continuous implantable electrodes within the muscle have been shown to prevent atrophy in denervated muscle in both animal (108,109) and human models (1). Despite mostly positive outcomes found with electrical stimulation applied at or within close proximity to the injury, some studies have reported conflicting outcomes when the electrical stimulation is applied at more indirect locations. Cohan investigated pulsed electrical current applied to the soma and demonstrated suppression of growth cone advancement and motility as a result (110). Chronic functional electrical stimulation of denervated muscle has also been shown to interfere with the re-establishment of neuromuscular connections (111). Schimrigk et al. demonstrated a retarding effect on the regenerating nerve fibers in a rat model using exogenous monophasic stimulation to the muscle (112). Clearly, the efficacy of electrical stimulation in the management of nerve injury is not well established, especially in human models. Evidence would suggest that direct stimulation of the nerve may enhance regeneration but needs further exploration in human models. To date, there are no strong indications for the enhancement of nerve regeneration through indirect stimulation. REHABILITATION CONCEPTS Critical in the rehabilitation of patient s following peripheral nerve injury is the prevention of nerve tension caused by elongation. Clark et al. showed in a rat model (immediate and delayed epineurial repair) that an 8% elongation for 30 minutes will result in a 50% decrease in blood flow with substantial recovery, whereas a 15% elongation for the same 74

9 Advances in Physiotherapy 5 (2003) PERIPHERAL NERVE INJURY duration will lead to an 80% reduction with minimal recovery (56). They further conclude that for repairs of large nerves where vascular ingrowth is likely to be incomplete, elongation of more than 8% may cause ischemia that is detrimental to nerve regeneration. Excessive elongation (16 17%) will compromise blood flow and can even lead to mechanical failure or suture pull out (56). During normal human motion, longitudinal excursion of a nerve occurs as an extremity moves through an arc of motion. This is facilitated by the nerve s intrinsic elastic properties and the nerve s ability to glide through adjacent tissue. The amount of nerve excursion that results with range of motion of adjacent joints has been reported in the literature. For example, median nerve excursion can differ from 4.3 mm with simple elbow flexion to upwards of mm when elbow flexion is combined with wrist and digit extension (113,114). Given the risk of ischemia, suture disruption and mechanical failure, avoidance of excessive range of motion is critical following nerve injury. Gliding of a nerve through adjacent tissue is important in normal and pathological states. Scar tissue adhesions can tether a nerve, which prevents gliding and can lead to nerve compression and a traction neuropathy. Traction neuritis as a result of these scar tissue adhesions may develop following an injury or surgery. Therefore, encouragement of early post-operative nerve motion and gliding is appropriate. Butler advocates examination and nerve mobilization by using various positional techniques for the upper and lower extremities (115). Though beyond the scope of this article, these techniques would be a valuable reference tool in order to learn proper positioning for mobilization of specific peripheral nerves. At 3 weeks, the axonal sprouts have crossed the gap and the tensile strength of a wound closed by primary intention will be approximately 20% of normal (34). Dagum suggests that controlled mobilization may begin at this time lasting for 3 more weeks (34). Lee et al. recommended that early mobilization of an isolated nerve injury should be avoided until intraneural blood vessels have crossed the repair, which occurred at 3 weeks in a canine model (116). They also concluded that early motion tends to impede nerve regeneration by enhancing adhesion formation and delaying the revascularization process at neurorrhaphy (116). The literature would support post-operative immobilization for 3 weeks followed by another 3-week period of controlled mobilization avoiding tension to the repair. Immediate immobilization of the injured limb following nerve repair has been the traditional protocol. However, some suggest that passive motion and splinting may help to prevent muscular fibrosis during denervation (2). Kim et al. demonstrated the feasibility of 2 weeks of continuous passive motion (CPM) on the knee joint in rabbits after a popliteal nerve repair (117). Although most outcomes were similar and reasonable regarding nerve regeneration and CPM use, there was significantly slower nerve conduction velocity when compared to the control group (immobilization). This study, however, demonstrates that CPM may be used when there are associated traumatic injuries to other tissues that may benefit from its use. When using the CPM, the physiotherapist should be careful not to interfere with the nerve repair, while at the same time retaining the benefits of the CPM on the healing of muscles, tendons, ligaments and articular cartilage. CPM parameters should be set through an arc of motion that promotes gliding but does not cause tension to the injured nerve. Dagum & Parry suggest that sensory re-education can improve the results of nerve repair (34,118). Florence et al. demonstrated that sensory retraining improves sensory perceptual function in monkeys (40). An association between sensory re-education and good or excellent results following a nerve transfer in humans has also been reported (119). EVALUATION OF RECOVERY The results of peripheral nerve injury vary and depend on the following: type and extent of the injury, surgical factors and patient characteristics. The British Medical Research Council Nerve Injury Committee classification scheme for sensory and motor recovery (34) and the Medical Research Council Grading System for Nerve Recovery (120), are helpful grading systems for determining the results of nerve injury (Tables II and III). Both scales grade nerve recovery on a continuum from M0 to M5 for motor and S0 to S4 for sensory. M0 indicates no evidence of muscle contraction, whereas M5 indi- 75

10 M. LANDERS & P. ALTENBURGER Advances in Physiotherapy 5 (2003) TABLE II: Nerve recovery grading system (34) Motor recovery Sensory recovery M0 No contraction S0 Absence of sensation M1 Contraction without movement S1 Recovery of deep cutaneous pain M2 Active movement with gravity eliminated S2 Return of some degree of superficial cutaneous pain and tactile sensation M3 Active movement against gravity S3 Return of superficial cutaneous pain and tactile sensation throughout the innervation area M4 Active movement against resistance S3+ Recovery with some 2-point discrimination M5 Normal power S4 Complete recovery TABLE III: Medical Research Council Grading System for Nerve Recovery (120) Motor recovery Sensory recovery M0 No contraction S0 No recovery M1 Return of perceptible contraction in the proximal S1 Recovery of deep cutaneous pain muscles S1+ Recovery of superficial pain M2 Return of perceptible contraction in the proximal S2 Recovery of superficial pain and some touch and distal muscles S2+ As in S2, but with over-response M3 Return of function in proximal and distal muscles S3 Recovery of pain and touch sensibility with disappearto such a degree that all important muscles are ance of over-response sufficiently powerful to act against gravity S3+ As in S3, but localization of the stimulus is good, and there is imperfect recovery of two-point discrimination M4 All muscles act against strong resistance, and some S4 Complete recovery M5 independent movements are possible Full recovery of all muscles cates a full recovery of denervated muscle. Likewise, S0 indicates no sensation and S4 indicates full sensory recovery. While both scales are similar, the definitions and grading have subtle differences. Logically, physiotherapists should utilize one scale for consistent grading. Dagum suggests that useful functional recovery, defined as discriminative sensation and complex movement, is a grade S3 (Return of superficial cutaneous pain and tactile sensation throughout the innervation area) or better for sensory nerves and M4 (Active movement against resistance) or better for motor nerves (Table II) (34). Generally, distal nerve injuries are more likely to heal faster and to a greater extent than proximal nerve injuries (34). Furthermore, younger patients have shorter regeneration distances, improved healing and greater capacity for cortical reorientation (34,119,121,122). Generally, pure sensory or pure motor nerve repair have better outcomes than mixed nerve repair, as do early repairs, short nerve grafts and clean nerve transactions (34,119). SUMMARY Treatment of the patient with a peripheral nerve injury begins with a strong understanding of nerve anatomy, pathophysiology and clinical presentation. The peripheral nerve structure and blood supply represent two important elements for understanding surgical interventions and post-operative treatment. The physiotherapist can maximize outcomes with intervention approaches by maintaining a strong awareness of these critical areas. Advancements in surgical repair and growth enhancement are important areas to understand. Physiotherapists may be the initial impetus for medical intervention in cases where a significant musculoskeletal injury masks an underlying traumatic 76

11 Advances in Physiotherapy 5 (2003) PERIPHERAL NERVE INJURY nerve injury. An exceptional understanding of the problems associated with peripheral nerve injury, including the delays in manifestations, should provide the physiotherapist with the knowledge of when to refer potential surgical candidates. In the case of Sunderland fourth-, fifth- and sixth-degree injuries, the physiotherapist plays a vital role in staging the level of these injuries and their appropriateness for referral back to the physician for possible surgical management. In addition, physiotherapists need to be patient advocates with regards to treatment interventions that can enhance or optimize nerve regeneration, e.g. direct current electrical fields. In addition, therapists can be advocates to prevent unwanted treatment that may actually prevent regeneration. Following surgery, the physiotherapist plays a significant role in the recovery of function. Movement to prevent tethering of the surgically repaired nerve is imperative, but ischemia and excessive elongation must be avoided. Movement to maintain the longitudinal excursion and gliding of the nerve will decrease the development of scar tissue formation, which otherwise may lead to tethering followed by a superimposed traction injury. Therefore, a supervised ROM program is needed with the caveat that significant education is required for patients to avoid compromising ranges early in the rehabilitative process. CPM use is a common tool but must be monitored for use that could be excessive and potentially deleterious. There is much in the literature devoted to the medical management of peripheral nerve injury. However, there is little evidence in the literature that supports physiotherapy intervention and outcome. Physiotherapists need to continue to advance their knowledge within this field to provide the most accurate and effective treatment for its patients. Outcome research particularly in this area is imperative to refine physiotherapy intervention and provide valid rehabilitation protocols in the management of peripheral nerve injury. REFERENCES 1. Nicolaidis SC, Williams HB. Muscle preservation using an implantable electrical system after nerve injury and repair. Microsurgery 2001;21: Diao E, Vannuyen T. Techniques for primary repair. Hand Clin 2000;16: Flores AJ, Lavernia CJ, Owens PW. Anatomy and physiology of peripheral nerve injury and repair. Am J Orthop 2000;29: Sunderland S, Bradley KC. The cross-sectional area of peripheral nerve trunks devoted to nerve fibers. Brain 1949;72: Breidenbach WB, Terzis JK. The blood supply of vascularized nerve grafts. J Reconstr Microsurg 1986;3: Lundborg G, Rydevik B. Effects of stretching the tibial nerve of the rabbit, A preliminary study of the intraneural circulation and the barrier function of the perineurium. J Bone Joint Surg 1973;55B: Mitchell JR, Ostermann AL. Physiology of nerve repair: a research update. Hand Clin 1991;7: Seddon HJ, Medawar PB, Smith H. Rate of regeneration of peripheral nerves in man. J Physiol 1943;102: Sunderland S. A classification of peripheral nerve injuries producing loss of function. Brain 1951;74: Mackinnon SE, Hudson AR. Clinical application of peripheral nerve transplantation. Plast Reconstr Surg 1992;90: Mackinnon SE. New directions in peripheral nerve surgery. Ann Plast Surg 1989;22: Ducker TB, Kempe LG, Hayes GJ. The metabolic background for peripheral nerve surgery. J Neurosurg 1969;30: Lieberman AR. The axon reaction: a review of the principal features of perikaryal responses to axon injury. Int Rev Neurobiol 1971;14: Fawcett JW, Keynes RJ. Peripheral nerve regeneration. Annu Rev Neurosci 1990;13: Mira JC. Effects of repeated experimental localized freezings in the distal stump of peripheral nerve. Clin Plast Surg 1984;11:

12 M. LANDERS & P. ALTENBURGER Advances in Physiotherapy 5 (2003) 16. Friede RL, Bischhausen R. The fine structure of stumps of transected nerve fibers in subserial sections. J Neurol Sci 1980;44: McQuarrie IG. Effect of a conditioning lesion on axonal sprout formation at nodes of Ranvier. J Comp Neurol 1985;231: Meller K. Early structural changes in the axoplasmic cytoskeleton after axotomy studied by cryofixation. Cell Tissue Res 1987;250: Yamada KM, Spooner BS, et al. Ultrastructure and function of growth cones and axons of cultured nerve cells. J Cell Biol 1971;49: Son YJ, Thompson WJ. Schwann cell processes guide regeneration of peripheral axons. Neuron 1995;14: Thomas PK. The cellular response to nerve injury. J Anat 1966;100: Beuche W, Friede RL. The role of non-resident cells in Wallerian degeneration. J Neurocytol 1984;13: Perry VH, Brown MC. Macrophages and nerve regeneration. Curr Opin Neurobiol 1992;2: Danielsen N, Varon S. Characterization of neurotrophic activity in the silicone-chamber model for nerve regeneration. J Reconstr Microsurg 1995;11: Funakoshi H, Frisen J, Barbany G, et al. Differential expression of mrnas for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol 1993;123: Heumann R, Korsching S, Brandtlow C, Thoenen H. Changes of nerve growth factor synthesis in nonneuronal cells in response to sciatic nerve transection. J Cell Biol 1987;104: Richardson PM, Lu X. Inflammation and axonal regeneration. J Neurol 1994;241(1 Suppl 1): Taniuchi M, Clark HB, Johnson EM. Induction of nerve growth factor receptor in Schwann cells after axotomy. PNAS 1986;83: Mackinnon S, Dellon AL, Lundborg G, Hudson A, Hunter DA. A study of neurotropism in the primate model. J Hand Surg [Am] 1986;11: Seckel B, Ryan S, Gagne R, et al. Target specific nerve regeneration through a nerve guide in the rat. Plast Reconstr Surg 1986;78: Brushart TM. Preferential reinnervation of motor nerves by regenerating motor axons. J Neurosci 1988;8: Brushart TM, Gerber J, Kessens P, Chen YG, Royall RM. Contributions of pathway and neuron to preferential motor reinnervation. J Neurosci 1998;18: Brushart TM, Seiler WA. Selective reinnervation of distal motor stumps by peripheral motor axons. Exp Neurol 1987;97: Dagum AB. Peripheral nerve regeneration, repair, and grafting. J Hand Ther 1998;11: Bowden R, Gutmann E. Denervation and reinnervation of human voluntary muscle. Brain 1944;67: Fu SY, Gordon T. Contributing factors to poor functional recovery after delayed nerve repair: prolonged denervation. J Neurosci 1995;15: Jabaley ME, Burns JE, et al. Comparison of histologic and functional recovery after peripheral nerve repair. J Hand Surg [Am] 1976;1: Mackinnon SE, Dellon AL. Clinical nerve reconstruction with a bioabsorbable polyglycolic acid tube. Adv Plast Reconstr Surg 1990;85: Hökfelt T, Zhang X, Wiesenfeld-Hallin Z. Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci 1994;17: Florence SL, Boydston LA, Hackett TA, Lachoff HT, Strata F, Niblock MM. Sensory enrichment after peripheral nerve injury restores cortical, not thalamic, receptive field organization. Eur J Neurosci 2001;13:

13 Advances in Physiotherapy 5 (2003) PERIPHERAL NERVE INJURY 41. Wall JT, Kaas JH. Long-term cortical consequences of reinnervation errors after nerve regeneration in monkeys. Brain Res 1986;372: Wall JT, Kaas JH, Sur M, et al. Functional reorganization in somatosensory cortical areas 3b and 1 of adult monkeys after median nerve repair. Possible relationships to sensory recovery in humans. J Neurosci 1986;6: Sanes JN, Suner S, Donoghue JP. Dynamic organization of primary motor cortex output to target muscles in adult rats. I. Long-term patterns of reorganization following motor or mixed peripheral nerve lesions. Exp Brain Res 1990;79: Bolesta MJ, Garrett Jr WE, et al. Immediate and delayed neurorrhaphy in a rabbit model: A functional, histologic, and biochemical comparison. J Hand Surg [Am] 1988;13: Grabb WC. Median and ulnar nerve suture. An experimental study comparing primary and secondary repair in monkeys. J Bone Joint Surg [Am] 1968;50: Van Beek A, Glover JL, et al. Primary versus delayed-primary neurorrhaphy in rat sciatic nerve. J Surgical Res 1975;18: Birch R, Raji AR. Repair of median and ulnar nerves, Primary suture is best. J Bone Joint Surg [Br] 1991;73: Merle M, Amend P, et al. Microsurgical repair of peripheral nerve lesions. Peripheral nerve repair and regeneration 1986;2: Vastamäki M, Kallio PK, et al. The results of secondary microsurgical repair of ulnar nerve injury. J Hand Surg [Br] 1993;18: Levinthal R, Brown WJ, Rand RW. Comparison of fasicular, interfasicular, and epineural suture techniques in the repair of simple nerve lacerations. J Neurosurg 1977;47: Young L, Wray RC, Weeks PM. A randomized prospective comparison of fasicular and epineural digital nerve repairs. Plast Reconstr Surg 1981;68: Bora FW. A comparison of epineural, perineural, and epiperineural methods of nerve suture. Clin Orthop 1978;133: Bora FW, Pleasure DE, Didizian NA. A study of nerve regeneration and neuroma formation after nerve suture by various techniques. J Hand Surg 1976;1: Grabb WC, Bement SL, Koepke GH, Green RA. Comparison of methods of peripheral nerve suturing in monkeys. Plast Reconstr Surg 1970;46: Terris DJ, Fee Jr WE. Current issues in nerve repair. Arch Otolaryngol Head Neck Surg 1993;119: Clark WL, Trumble TE, Swiontkowski MF, Tencer AF. Nerve tension and blood flow in a rat model of immediate and delayed repairs. J Hand Surg 1992;17: Bora FW, Richardson S, Black J. The biomechanical responses to tension in a peripheral nerve. J Hand Surg 1980;5: Terzis JK, Faibisoff BA, Williams B. The nerve gap: suture under tension versus graft. Plast Reconstr Surg 1975;56: Mackinnon SE. Surgical management of the peripheral nerve gap. Clin Plast Surg 1989;16: Mackinnon SE. Nerve allotransplantatioin following severe tibial nerve injury: case report. J Neurosurg 1996;84: Marmor L. Peripheral nerve grafts. Clin Neurosurg 1970;17: Sanders FK, Young JZ. The degeneration and re-innervation of grafted nerves. J Anat 1941;76: Chiu DTW, Janecka I, Krizek TJ, Wolff M, Lovelace RE. Autogenous vein graft as a conduit for nerve regeneration. Surgery 1982;91: Chiu DTW, Strauch B. A prospective clinical evaluation of autogenous vein grafts used as a nerve conduit for distal sensory nerve defects of 3cm or less. Plast Reconstr Surg 1990;86: