Peripheral nerve repair and reconstruction

Gross anatomy: the upper extremity

The brain and the spinal cord (central nervous system) are connected to targets by the peripheral nervous system, which consists of cranial nerves, spinal nerves with roots and rami, and peripheral nerve trunks with the peripheral components of the autonomic nervous system. The anterior and posterior nerve roots (that emerge from rootlets attached to the spinal cord) merge into the spinal nerve, where the anterior primary rami form the brachial plexus in the upper extremity ( Fig. 22.1 ). The posterior primary ramus runs posteriorly, and supplies the muscle and skin of the posterior part of the neck and trunk; it does not enter the extremity. The anterior primary rami of the cervical nerve roots C5–C8 and the ramus of T1 form the brachial plexus, from which the upper extremity receives its innervation through various branches.

C5–C6 form the upper trunk of the brachial plexus, C7 forms the middle trunk, and C8–T1 form the inferior trunks. These trunks divide into anterior and posterior divisions in which the lateral and medial cords are formed from the anterior division, while the posterior divisions form the posterior cord, which mainly innervates the extensor muscles in the upper extremity. In contrast, the lateral and medial cords innervate the flexor muscles in the extremity. The musculocutaneous nerve originates from the lateral cord. The median nerve is formed by the joining of the lateral and medial cords, whereas the ulnar nerve branches from the medial cord together with the medial cutaneous nerves to the arm (brachial) and forearm (antebrachial). The radial and axillary nerves originate from the posterior cord. There is a segmental pattern of sensory and motor innervation ( Fig. 22.2 ).

The anatomy of the plexus and the nerve trunks may vary considerably from person to person. Variations are seen in the forearm, where a “Martin Gruber” anastomosis may be found in as many as 15%, particularly between the anterior interosseous nerve and the ulnar nerve. A similar anastomosis may also be present more distally – Riche–Cannieu branch between the motor branch of the ulnar nerve and the thenar branch of the median nerve in the thenar region in the hand. Another common and consistent variant is the palmar communicating branch according to Berrettini ( Fig. 22.3 ).

The neuron and supporting cells

The cell bodies of the motor and sensory neurons are located in the spinal cord and in the dorsal root ganglia, respectively, with their axons extending out to their respective targets in the periphery. The sensory neuron is pseudounipolar, with one branch of the axon extending into the posterior part of the spinal cord. The transition from the central to the peripheral nervous system takes place in the rootlets (or less often, in roots of the nerves) of the transitional zone, which are almost cone-shaped. In the central part, the neurons are surrounded by oligodendrocytes and astrocyte processes, whereas in the peripheral nervous system axons are closely associated with Schwann cells. In myelinated nerve fibers, each axon is embraced by a series of continuous Schwann cells that create the myelin sheath. The border between individual and enwrapping Schwann cells is called the node of Ranvier (see Fig. 22.4 ). Each nerve fiber is enclosed in a basal lamina (or basement membrane). In contrast, several thinner axons run in troughs in one Schwann cell – nonmyelinated nerve fibers. Each Schwann cell therefore embraces several axons. The diameter of nerve fibers varies, and extends from 0.4 to 1.25 µm (nonmyelinated) and from 2 to 22 µm (myelinated). The number of nerve fibers also varies with nerve trunks. In addition, the number of nerve fibers decreases with age: as many as 26% of the nerve fibers may disappear between the second and eighth decades.

The nerve trunk

A number of nerve fibers are enclosed in bundles around which there are flattened supporting cells and layers of collagen that form the perineurium. These bundles of fibers surrounded by the perineurium are called fascicles, which are embedded in loose connective tissue (called epineurium); this is composed of collagen fibers and fibroblasts ( Figs. 22.4 & 22.5 ). The space inside the fascicles is called the endoneurial space, in which the pressure is slightly positive (endoneurial fluid pressure); it consists of collagen fibrils, and cells, such as fibroblasts and occasional macrophages and mast cells. Lymphocytes (CD4 ⁺ and CD8 ⁺ ) and macrophages are not generally found in the endoneurium (except after injury), but may be present in the epineurium. The amount of connective tissue varies among nerve trunks, and also within the same nerve trunk. More abundant connective tissue is therefore located in the nerve trunk at sites where extra protection is needed (such as joints and superficial nerve trunks). The term “mesoneurium” refers to the additional loose areolar tissue that is located superficially to the epineurium. This tissue allows for the gliding of the nerve trunk (excursion) during movements of the extremity.

There is topographical segregation of fascicles and nerve fibers in the nerve trunks, particularly in their peripheral parts. The latter anatomical feature permits dissection of a bundle of fascicles that can be used in nerve transfers.

Blood supply

Nerve trunks receive their blood supply from segmental blood vessels ( Fig. 22.6 ), which branch into plexuses in the epineurium, perineurium, and in the endoneurial space. The blood vessels inside the fascicles consist mainly of capillaries, which are provided by circulation through blood vessels that pierce the perineurium obliquely. The epineurial blood vessels are more susceptible to trauma than the endoneurial vessels and so epineurial edema develops more easily than endoneurial edema. Because of the extensive reserve capacity of the intraneural blood supply it is possible to mobilize a nerve over an extended length without disturbing the blood supply. In addition, the blood vessels adjacent to the nerve trunks have a coiled appearance that allows excursion of the nerve trunk. In addition to the vasa nervorum, there are also nervi nervorum, such as free nerve endings in the epineurium, perineurium, and endoneurium.

Degeneration and regeneration

After a nerve injury, deep and intense processes are initiated in the injured neurons and their axons and in the non-neuronal cells, particularly the Schwann cells. In the cells a number of temporary and spatially orchestrated mechanisms guide survival and regeneration. In addition, there are mechanisms that lead to apoptosis of the cells. The signal transduction processes are not clarified, and this is a target of intense research. After the peripheral nerve trunk has been injured by transection or avulsion, the proximal part of the axon is resealed to form a new surface on the tip of the axon – a process that is influenced by the presence of calcium. There is usually a slight retraction of the proximal axon, which is related to the number of injured Schwann cells. At the tip of the axon, signals are formed in the signal transduction processes and transferred to the nucleus of the neuron where the functions are changed from maintenance to survival and growth.

The distal nerve segment

Schwann cells are extremely important for the function of the peripheral nerve, both in the normal state and after injury. After injury there is disintegration of the axons and the myelin sheath in the distal nerve segment, the latter released by Schwann cells. It is important to remove myelin and the disintegrated axon to allow and prepare a conducive environment for the regenerating axons. Both macrophages and Schwann cells can therefore contribute to the cleaning-up mechanisms, where their relevance varies over time.

The timing of nerve repair is of crucial importance for a successful outgrowth of axons after injury, which can be related to a large number of factors that are up- and downregulated by Schwann cells after nerve injury. After the Schwann cells have been activated they proliferate along the inside of their basal lamina, and form the bands of Büngner.

Neurotrophic factors and their receptors are upregulated in Schwann cells after injury, and these may include neurotrophins (such as nerve growth factor and brain-derived neurotrophic factor), fibroblast growth factors (such as β-fibroblast growth factor), neuropoietic cytokines (such as ciliary neurotrophic factor and leukemia-inhibitory factor), and other groups of factors, such as insulin-like growth factor, transforming growth factor, and interleukins.

Apoptosis (programmed death) of various cells, such as macrophages and Schwann cells, an event that is initiated by release of proapoptotic molecules from the mitochondria (intrinsic pathway), can be activated through the death cell surface receptors (extrinsic pathway; like Fas and tumor necrosis factor receptor 1). The number of apoptotic Schwann cells in the distal nerve segment is increased if the transected nerve is repaired after a delay.

All these changes in the injured neuron and its axon and in the Schwann cells have the common goal of regrowth of the axons into the distal nerve segments down to their targets. Regrowth is a delicate process in which numerous sprouts emerge from the distal part of each axon. On the tip of each sprout there is a growth cone, which is formed as a small hand on which the “finger-like” filopodia palpate the environment with the purpose of finding guidance structures ( Fig. 22.7 ). Intricate mechanisms direct rate and direction of extension of the growth cones, where actin filaments are polymerized and organized. Microtubules are polymerized in the growth cones. The growth is a dynamic process, where the filopodia/growth cone is repulsed or attracted depending on the local mechanisms and the structure of the environment.

The extracellular matrix is extremely important for the outgrowth and advancement of the growth cone. Proteins, such as laminin, fibronectin, galactins, tenascin, and collagens, stimulate outgrowth. Laminin exerts its stimulatory effect through cell surface glycoproteins called integrins, which interact with the intracellular actin in the growth cone and in the filopodia, thus navigating outgrowth of the axon. Precise knowledge about how axons grow and how growth is directed is still limited.

First-degree injury

In neuropraxia there is a physiological block of conduction, but no disruption of the neural architecture at the site of injury, and there are no degenerative changes within the nerve. The pathogenesis is most often external compression, surgical traction, or local ischemia. Complete recovery is the general rule, and the healing time can vary from a few days to 3–4 months. Tinel’s sign is not present over the site of injury.

Second-degree injury

In second-degree injuries, true degeneration of axons is initiated. Axonal damage leads to distal (Wallerian) degeneration, although the basal lamina of the Schwann cells remains intact. The axons regenerate through their own endoneurial tubes by axonal contact and guidance of the regenerating growth cones at a rate of 1–3 mm/day. No topographical mismatch will occur, and the integrity of sensory and motor nerve fibers remains intact. Tinel’s sign is present, and the progress of recovery can by followed by the gradual recovery of motor or sensory function distal to the injury. Full recovery is expected.

Third-degree injury

In a third-degree injury the architecture within the perineurium is disrupted together with axonal damage. The fascicles remain intact, although progression of axonal regrowth will be with less precision as the axonal guidance is impaired and mismatch of fibers will occur. Axonal mismatch follows to a larger extent in proximally based injuries as the fascicular organization is usually of mixed motor and sensory patterns. The clinical outcome is hard to predict, mainly because of subsequent intrafascicular scarring and the failure of some axons to regenerate. Tinel’s sign is present and progresses distally with recovery. Microsurgical resection and grafting may not always be beneficial in these cases.

Fourth-degree injury

In a fourth-degree lesion the epineurium is intact, but all other parts of the nerve are damaged. The formation of an intraneural scar impairs both axonal regeneration and reinnervation, and typically forms a neuroma at the site of injury. A more profound retrograde neuronal effect than in a third-degree injury is expected, and this causes a higher incidence of neuronal death. Tinel’s sign is usually present over the site of the injury, but there are no signs of recovery, or proximal-to-distal progression of regeneration. The injury requires complete excision of the neuroma and microsurgical nerve repair, usually with nerve grafting.

Fifth-degree injury

In a fifth-degree injury the nerve is completely transected. Recovery of function is dependent on surgical repair, with or without nerve grafting. These injuries are most commonly associated with injuries that include the surrounding structures, such as tendons, muscles, bones, or blood vessels.

Sixth-degree injury

The sixth-degree injury was added by Mackinnon to take account of mixed injuries, for example those that occur after closed traction damage to a nerve, or gunshot or stab wounds that cause partial injuries to a nerve. This type of injury is often referred to as a neuroma-in-continuity, in which all degrees of nerve injury, from normal to neurotmesis, may coexist within the scarred nerve. A neuroma in continuity typically results from failure of the regenerating nerve growth cone to proceed beyond the injury to reach its peripheral targets. It occurs within an intact nerve with continuity in response to internally damaged axons and fascicles, resulting in a distal portion of the nerve that no longer, more or less, functions properly. Surgical exposure is often necessary and intraoperative electrodiagnostic studies can help to distinguish fascicles with signs of recovery from those without (grades IV and V).