Peripheral Nerve Injury and Repair Steve K. Lee, MD, and Scott W. Wolfe, MD Abstract Peripheral nerve injuries are common, and there is no easily available formula sheath. The perineurial layer is the for successful treatment. Incomplete injuries are most frequent. Seddon classi- major contributor to nerve tensile fied nerve injuries into three categories: neurapraxia, axonotmesis, and neu- strength. The endoneurium is the rotmesis. After complete axonal transection, the neuron undergoes a number of innermost loose collagenous matrix degenerative processes, followed by attempts at regeneration. A distal growth within the fascicles. Axons run cone seeks out connections with the degenerated distal fiber. The current surgi- through the endoneurium and are cal standard is epineurial repair with nylon suture. To span gaps that primary protected and nourished by this repair cannot bridge without excessive tension, nerve-cable interfascicular auto- layer.1 grafts are employed. Unfortunately, results of nerve repair to date have been no Sunderland has demonstrated better than fair, with only 50% of patients regaining useful function. There is that fascicles within major peripheral much ongoing research regarding pharmacologic agents, immune system modu- nerves repeatedly divide and unite lators, enhancing factors, and entubulation chambers. Clinically applicable to form fascicular plexuses.1 This developments from these investigations will continue to improve the results of leads to frequent changes in the treatment of nerve injuries. cross-sectional topography of fas- J Am Acad Orthop Surg 2000;8:243-252 cicles in the peripheral nerves. In general, the greatest degree of fascic- ular cross-branching occurs in the lumbar and brachial plexus regions. Peripheral nerves were first distin- these strategies involve the use of Several studies have demonstrated guished from tendons by Heroph- pharmacologic agents, immune sys- greater uniformity of fascicular ilus in 300 BC. By meticulous dis- tem modulators, enhancing factors, arrangement in the major nerves of section, he traced nerves to the and entubulation chambers. A thor- the extremities; in fact, the palmar spinal cord, demonstrating the con- ough understanding of the basic cutaneous and motor branches of tinuity of the nervous system.1 In concepts of nerve injury and repair the median nerve may be dissected 900 AD, Rhazes made the first clear is necessary to evaluate the contro- proximally for several centimeters reference to nerve repair. How- versies surrounding these innova- without significant cross-branching. ever, not until 1795 did Cruikshank tive new modalities. demonstrate nerve healing and recovery of distal extremity func- tion after repair. In the early 1900s, Anatomy Dr. Lee is Major, United States Air Force, Cajal pioneered the concept that Section of Orthopaedic Surgery, Walson Air axons regenerate from neurons and The cross-sectional anatomy of a Force Hospital, Fort Dix, NJ. Dr. Wolfe is Professor and Director, Hand and Upper are guided by chemotrophic sub- peripheral nerve is demonstrated in Extremity Center, Department of Orthopaedics stances. In 1945, Sunderland pro- Figure 1. The epineurium is the and Rehabilitation, Yale University School of moted microsurgical techniques to connective tissue layer of the pe- Medicine, New Haven, Conn. improve nerve repair outcomes.1 ripheral nerve, which both encircles Since that time, there have been a and runs between fascicles. Its main Reprint requests: Dr. Wolfe, Department of Or- number of advances and new con- function is to nourish and protect thopaedics and Rehabilitation, Yale University School of Medicine, 800 Howard Avenue, New cepts in peripheral nerve recon- the fascicles. The outer layers of the Haven, CT 06510. struction. Research regarding the epineurium are condensed into a molecular biology of nerve injury sheath. Within and through the Copyright 2000 by the American Academy of has expanded the available strate- epineurium lie several fascicles, Orthopaedic Surgeons. gies for improving results. Some of each surrounded by a perineurial Vol 8, No 4, July/August 2000 243 Peripheral Nerve Injury and Repair nerve does not undergo distal de- Epineurium generation. Axonotmesis is defined Perineurium as a loss of continuity of axons, with Endoneurium variable preservation of the connec- Axon tive tissue elements of the nerve. Neurotmesis is the most severe injury, equivalent to physiologic dis- ruption of the entire nerve; it may or may not include actual nerve tran- section. After injury (short of tran- section), function fails sequentially in the following order: motor, proprio- ception, touch, temperature, pain, and sympathetic. Recovery occurs Schwann cell Node of Ranvier sequentially in the reverse order. Sunderland1 further refined this Myelin sheath classification on the basis of the real- Axon ization that axonotmetic injuries had widely variable prognoses. He di- vided Seddon’s axonotmesis grade into three types, depending on the degree of connective tissue involve- Figure 1 Cross-sectional anatomy of the peripheral nerve. Inset at left shows an unmye- ment. Neurapraxia is equivalent to a linated fiber. Inset at bottom shows a myelinated fiber. (Adapted with permission from Lundborg G: Nerve Injury and Repair. New York: Churchill Livingstone, 1988, p 33.) Sunderland type 1 injury. Complete recovery follows this injury, which may take weeks to months. In a Sunderland type 2 injury, the In nerve repair, fascicular matching which accommodates strain and endoneurium, perineurium, and is critical to outcome, and strategies gliding of the nerve during motion.1 epineurium are still intact, but the for achieving this will be discussed. Endoneurial capillaries have the axons are physiologically disrupted. The blood supply of peripheral structural and functional features of Because the endoneurium is intact, nerves is a complex anastomotic the capillaries of the central nervous the regenerating axons are directed network of blood vessels (Fig. 2). system and function as an extension along their original course, and There are two major arterial systems of the blood-brain barrier. The en- complete functional recovery can be and one minor longitudinal system dothelial cells within the capillaries expected. The time for recovery de- linked by anastomoses. The first of the endoneurium are intercon- pends on the level of injury, as the major system lies superficially on nected by tight junctions, creating a axon must regenerate distally to the the nerve, and the second lies with- system that is impermeable to a end-organ. It can usually be mea- in the interfascicular epineurium. wide range of macromolecules, sured in months, as opposed to The minor longitudinal system is including proteins. This barrier is weeks for a Sunderland type 1 injury. located within the endoneurium impaired by ischemia, trauma, and Injuries to subsequent connective and perineurium. The major super- toxins, as well as by the mast-cell tissue layers upgrade the Sunder- ficial longitudinal vessels maintain a products histamine and serotonin. land classification. relatively constant position on the In a Sunderland type 3 injury, the surface of the nerve. The segmental endoneurium is also disrupted, but vascular supply consists of a num- Injury Classification the perineurium and epineurium ber of nutrient arteries that vary in are intact. Recovery is incomplete size and number and enter the nerve Seddon2 classified nerve injuries into in this grade of injury for a number at irregular intervals. They repeat- three major groups: neurapraxia, of reasons. First, there is more se- edly branch and anastomose with axonotmesis, and neurotmesis vere retrograde injury to cell bodies, the internal longitudinal system to (Table 1). Neurapraxia is character- which either destroys neurons or create an interconnected system. In- ized by local myelin damage, usual- slows their recovery. Second, with- jection studies have revealed the rel- ly secondary to compression. Axon out an intact endoneurium, intrafas- ative tortuosity of the blood vessels, continuity is preserved, and the cicular fibrosis occurs, which hin- 244 Journal of the American Academy of Orthopaedic Surgeons Steve K. Lee, MD, and Scott W. Wolfe, MD Physiology of Nerve Vascular plexa Degeneration in epineurium Following axonal transection, a se- quence of pathologic events occurs in the cell body and axon. The cell body swells and undergoes chro- matolysis, a process in which the Nissl granules (i.e., the basophilic neurotransmitter synthetic machin- ery) disperse, and the cell body be- comes relatively eosinophilic. The Vascular system cell nucleus is displaced peripher- in endoneurium ally. This reflects a change in meta- Regional nutrient bolic priority from production of vessel neurotransmitters to production of structural materials needed for Extrinsic axon repair and growth, such as vessel messenger RNA, lipids, actin, tubu- Vascular system lin, and growth-associated proteins. in perineurium Shortly after axonal transection, the proximal axon undergoes trau- Figure 2 Blood supply of a peripheral nerve. (Adapted with permission from Lundborg matic degeneration within the zone G: Nerve Injury and Repair. New York: Churchill Livingstone, 1988, p 43.) of injury (Fig. 3). In most instances, the zone of injury extends proxi- mally from the injury site to the next node of Ranvier, but death of ders axonal regeneration. Third, Sunderland’s classification accurate- the cell body itself may occur, de-