Introduction and Historical Notes

The peripheral nervous system (PNS) embodies unique anatomical structure and function that contributes immensely to human quality of life. Through the ages, the importance of the PNS has been recognized, but function and structure were often misinterpreted or considered mystical. The Alexandrians, specifically Herophilus of Chalcedon (335–280 bc ) and Erasistratus of Chios (310–250 bc ) are credited with differentiating nerves from tendons and even proposed the presence of different nerves for motor and sensory functions. Erasistratus distinguished nerves, in addition to arteries and veins, as one of the three main channels in the body, but proposed that “animal spirits” flowed through the nerves, subserving sensation and movement. The electrical basis of nerve and muscle potentials was better realized after Arrhenius (1859–1927) and other physical chemists demonstrated the properties of ions in electrolyte solutions, and nerves and muscles were found to conform to membrane potentials predicted by the Nernst equation. Technological advances during the First World War allowed revelation of the properties of nerve action potentials. Continued advancement of our knowledge of the structure and function of the PNS, as well as the instruments to study it have allowed us to not only better understand PNS pathology, but intricately modify and repair it to better improve the human experience.

Anatomical Considerations

The PNS is composed of neurons and supporting glial cells called Schwann cells . Neurons may be motor, sensory, or mixed. The neuron cell bodies are located in the spinal cord, and long cytoplasmic peripheral extensions called axons carry electrical impulses to or from their targets. Axons are separated from one another via endoneurium, and organized groups of axons are called fascicles ( Fig. 24.1 ). The perineurium surrounds fascicles, and the internal epineurium separates the perineurial-ensheathed fascicles. The external epineurium encompasses all fascicles and the internal epineurium and establishes the nerve silhouette. The mesoneurium is located external to the epineurial layers, is continuous with the perineurium, and is critical in longitudinal gliding of the nerve. Schwann cells (SCs) are subdivided into two main types: myelinating SCs and non-myelinating SCs. Myelinating SCs insulate and protect axons by iteratively wrapping their membranes to form the multilaminated myelin sheath, ensuring that nerve impulses travel quickly and efficiently. Independent of their functions in myelination, Schwann cells also provide vital trophic support to neurons. Loss of myelin can lead to permanent neuron loss, significant pain, and morbidity, and ultimately paralysis. Non-myelinating SCs are located along axons and at the neuromuscular junction and provide many functions including trophic support, phagocytosis, synaptic transmission, and support for reinnervation. More knowledge regarding the importance of non-myelinating SCs is evolving constantly.

Figure 24.1, Nerve anatomy.

Fascicular nerve patterns may be monofascicular with just one large fascicle; oligofascicular , consisting of a few fascicles; and polyfascicular, consisting of many fascicles of varying sizes. In the proximal extremities a monofascicular pattern predominates, consisting of both motor and sensory nerves with considerable plexus formation among fascicles. Moving more distally, the plexus formation simplifies and a more specific, polyfascicular pattern with differentiation into motor and sensory regions closer to the end-target, is found.

Knowledge of internal nerve topography allows specific fascicular alignment during repair to enhance efficiency and specificity of recovery. Topography for specific nerves has been described and results from intraoperative electrical stimulation to differentiate motor and sensory regions. Nerve transfers, such as the double fascicular transfer, are a direct application of the knowledge of internal topography.

The vascular supply for nerves is via two main systems, collectively referred to as the “vasa nervorum.” The mesoneurium provides the extrinsic vascularity, while the endoneurium houses the intrinsic nerve vascular supply. The extrinsic supply was described by Ranvier as early as 1878, upon which Ramage further elaborated. The intrinsic supply consists of fragile capillary networks that are easily disrupted. Vasa nervorum have been described in detail for specific nerves. The vasa nervorum are linked to injury and repair. Flow is increased in the extrinsic and intrinsic systems in the acute period following injury with angiogenesis occurring in the perineurium and epineurium approximately 2 weeks after injury in the rat model. After prolonged denervation (>6 months), vascular flow is diminished, and this phenomenon reverses after reinnervation.

Classification of Nerve Injury

Correct classification of nerve injury is paramount to planning appropriate management strategies. Establishing the degree of nerve injury predicts prognosis for recovery or lack thereof. In 1943, Seddon initially categorized nerve injury into neurapraxia, axonotmesis, and neurotmesis. This classification system was later elaborated by Sunderland in 1951, into five degrees of nerve injury, and he alluded to possible combinations of these degrees of injury. Mackinnon popularized the mixed pattern, or sixth degree, of injury, which describes multiple injury patterns at the same level ( Table 24.1 ).

Table 24.1
Degrees of nerve injury
Degree of injury Recovery Rate of recovery Surgical management Electrodiagnostic studies
Favorable
I Neurapraxia Complete Up to 12 weeks No fibrillations
II Axonotmesis Partial + 1 mm daily ± Fibrillations and MUPs
III Axonotmesis Partial 1 mm daily ± Fibrillations and MUPs
Unfavorable
IV Neuroma-in-continuity None None + Fibrillations, no MUPs
V Neurotmesis None None + Fibrillations, no MUPs
VI Mixed injury (I–V) Some fascicles (II, III) Varies with injury (I–V) + Varies with injury
MUPs, motor unit potentials.

Both first- and second-degree injuries can be grouped into favorable injuries, are expected to recover spontaneously, and therefore are typically managed conservatively. A first-degree injury, or “neurapraxia,” is an ischemic injury or conduction block which may have segmental demyelination, but no interruption of axons or surrounding connective tissue. As a result, no axonal degeneration occurs, and complete recovery is expected within 12 weeks after axonal remyelination is complete. In cases of chronic nerve compression, a permanent conduction block may ensue. Second-degree injuries, or “axonometric injuries,” involve axonal disruption but persistent continuity of surrounding connective tissue sheaths, including the basal lamina. The axons distal to the injury site undergo Wallerian degeneration, and recovery is expected in alignment with nerve regeneration at a rate of 1 mm daily. Motor nerve injuries distant to the target muscle may be at risk for incomplete recovery due to the deleterious microenvironment occurring with prolonged denervation in both the nerve and target muscle.

More severe peripheral nerve injuries require surgical intervention. Third-degree injuries are also axonometric injuries, with injury to both axons and the endoneurium. Fibrosis within the endoneurium prevents complete axonal regeneration and recovery. Surgical intervention to release scarred tissues or areas of entrapment is indicated to optimize functional recovery. In the absence of surgery, recovery is incomplete. Typically, outcomes following decompression are superior to excision of the injured nerve and grafting, except in cases of complex regional pain syndromes. Fourth- and fifth-degree injuries are unfavorable. Fourth-degree injuries, or “neuromas-in-continuity,” include injuries to axons, endoneurium, and perineurium. No potential for spontaneous recovery exists with fourth-degree injuries, and surgical intervention with neuroma excision and grafting is required. Superior long-term outcomes with neuroma excision and grafting, rather than neurolysis have been demonstrated in the example of birth-related brachial plexus injuries. Fifth-degree nerve injuries, or “neurotmesis,” result from complete nerve transection, or interruption of axons and all connective tissues (endoneurium, perineurium, and epineurium). Surgical management is required. Sixth-degree, or “mixed pattern injuries” describe nerve injuries that incorporate two or more injury patterns at the same level. These injury types are the most complex, as consideration must be given to all involved injury types with particular emphasis to not downgrade function.

The determination of nerve injury is often aided with electrodiagnostic studies. The second author (ASW) employs electromyography (EMG) to augment the clinical picture in patients with unclear degrees of injury. Fibrillations, which are indicative of nerve injury, appear within 4–6 weeks of injury, but motor unit potentials (MUPs), which result from adjacent axonal sprouting predict the capacity for spontaneous recovery, may not appear on EMG testing until 8–12 weeks after injury. EMG testing can, therefore, be employed 3 months from the time of injury to determine prognosis for spontaneous recovery. The absence of MUPs is an indication to proceed with surgical intervention. Motor unit potentials are not seen in fourth- and fifth-degree injuries, and may or may not be seen in third-degree injuries ( Table 24.1 ). EMG testing can be particularly helpful for determining prognosis in third-degree and mixed injuries.

Wallerian Degeneration and Neuroregeneration

Changes occur in both the proximal and distal neuron after injury. Dr Augustus Waller first described the “ alterations which take place in the elementary fibres of the nerve after they have been removed from their connection with the brain or spinal marrow ” in sections of the glossopharyngeal and hypoglossal nerves of the frog. Termed “Wallerian degeneration,” the distal axonal segment undergoes degenerative changes in which SCs, fibroblasts, myocytes, and injured axons express neurotrophic factors in response to injury as degrading neural elements are phagocytosed. Axons in the proximal segment undergo retraction and a brief dormant phase before formation of a regenerating unit. The regenerating unit elongates and sprouts multiple axon branches. Remaining endoneurial tubes termed “Bands of Bungner” and proregenerative Schwann cells guide axons to their targets. Extreme proximal axonal injuries and avulsions may lead to death of the cell body. Similar processes of Wallerian degeneration and neuroregeneration occur in the setting of nerve autografting and are required for proper regeneration across the graft. Increased knowledge of the molecular signaling events occurring during these degenerative and regenerative processes may lead to therapeutic interventions for management of neurodegenerative disorders.

Planning the Reconstruction

Timing of Nerve Repair/Reconstruction

Recovery following peripheral nerve injury is influenced not only by the degree of nerve injury, but also by the relative distance of the injury to the end-target. When planning motor reconstruction, consideration must be given to the timing of the nerve injury, timing and type of nerve repair or reconstruction, and required nerve regeneration distance for reinnervation of the target muscle. There is a critical window of approximately 12–18 months, during which functional reinnervation is possible following injury. Beyond this timeframe, muscle and nerve are unable to interface for a multitude of reasons.

After nerve injury, neurons, Schwann cells, and muscle all undergo changes in morphology and genetic expression to prepare and allow for regeneration to occur. Pre­viously, muscle was thought to be the primary contributor to poor recovery with prolonged denervation. Myofibril reabsorption, actin and myosin catabolism, increased collagen deposition in the extracellular space, and decreased muscle cell size occur due to proteasomes associated with the ubiquitin-proteasome pathway. Myocytes may undergo apoptosis, and muscle becomes less vascular due to capillary loss. These changes occur non-uniformly throughout muscle. Muscle fibers group with reinnervation, and although motor endplate number may increase in the re­maining viable muscle during reinnervation, functional recovery is poor. Loss of muscle cross-sectional area in denervation atrophy corresponds with decreased contractile force. With prolonged denervation, myofibril disorganization and collagen replacement result in decreased specific force capacity, which is permanent. Axons distal to the injury undergo fragmentation and Wallerian degeneration, with loss of their myelin sheath, as outlined above. Denervated SCs dedifferentiate to a less mature state that supports neuroregeneration and neuromuscular junction reinnervation. Prolonged denervation and axotomy periods, however, lead to progressively poor neuroregenerative conditions involving not only the muscle, but also the nerve. There is increasing evidence regarding the deleterious effect of SC senescence on neuroregeneration. The complete microenvironment, therefore, becomes less supportive for functional recovery with prolonged denervation.

It is this time-sensitivity for motor recovery that is integral for reconstructive planning. The time interval from injury to presentation to the peripheral nerve surgeon, as well as the location of the nerve lesion and its distance from the motor end-target, may preclude optimal or even feasible functional motor recovery via traditional methods. Proximal nerve injuries that are distant from their end-target may not be appropriate for reconstruction at the site of the lesion, even with immediate patient presentation. Nerve transfers provide a solution to this reconstructive challenge by reconstructing the deficit near the end-target rather than at a distant injury site. Nerve transfers are discussed further in a later section.

Sensory reinnervation is not limited by such time constraints, although the unfavorable microenvironment related to axons and SCs continues to be investigated. Currently, it is accepted that sensory reconstruction may be performed at any time and may traverse any distance, although the true boundaries of sensory reconstruction remain unknown.

Sensory Protection of Denervated Muscle

Given that time to motor reinnervation is inversely related to functional outcome, opportunities to provide protection for denervated muscle during the neuroregeneration period have been pursued. Protection of denervated muscle via sensory innervation has been described. Temporary or permanent sensory protection has demonstrated increased muscle mass, increased compound motor action potentials, and decreased levels of glial cell line-derived neurotrophic factor mRNA compared with unprotected controls, suggesting a trophic effect for denervated muscle fibers. Sensory-protected muscles demonstrate retained muscle fiber organization, a trend in increased motor endplate numbers, and reduction in muscle spindle degeneration. The functional benefits for sensory protection of denervated muscle remain uncertain, but clinical improvements have been reported by Bain et al. after saphenous nerve protection of the tibialis anterior branch of the peroneal nerve and the gastrocnemius branch of the tibial nerve in the setting of complete sciatic nerve palsy following total hip arthroplasty.

Principles of Nerve Repair

Equipment

Peripheral nerve surgery should be performed by an experienced or well-trained microsurgeon familiar with peripheral nerve anatomy and physiology, with the proper available equipment, team, and facilities. Nerve surgery is best performed with the use of the operating microscope with appropriate lighting, although some surgeons prefer the use of ≥4.0 loupe magnification. The neurotomy instrument set (S&T, USA) greatly facilitates cutting the nerve sharply ( Fig. 24.2 ) to maintain all fascicles in the same plane. We prefer 10-0 nylon with an atraumatic needle for perineurial suture and 10-0–8-0 nylon for epineurial sutures. Larger suture materials are not used, even when major nerves are being repaired. Suture materials for nerve repair allow approximation and alignment of the nerve ends, not strength to withstand tension. All nerve coaptations should be tension-free. Sharp-tip needles are imperative, and each needle should be used for only four or five stitches, since multiple passes through the nerve blunts the tip of the needle. Dull needle tips may dislodge delicate fascicles and prevent atraumatic needle passage. Fibrin may be used as a safe alternative to microsutures for neural coaptations, such as in birth-related brachial plexus surgery, where proximal stumps may be located within spinal foramina, or as reinforcement for a sutured neural coaptation.

Figure 24.2, (A,B) Victor Meyer neurotomy apparatus.

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