Neurotization

Neurotization can have two different meanings: On the one hand, the term neurotization is used to describe the healing of a damaged peripheral nerve. On the other hand, it describes the surgical transfer of peripheral nerves in particular to another target structure. Neurotization is intended to restore nerve supply to denervated muscle or nerve cells or other organ tissues. For example, if the target area is a muscle, the neurotization is usually performed for functional improvement after paralysis of individual peripheral nerves in order to reactivate the paralyzed muscle.^[1]

Denervated skin areas can result from traumatic (accidents), surgical, infectious and other causes, such as reduced blood circulation, autoimmune diseases or tumor growth. In addition to loss of sensation, dysfunction of the autonomic nervous system is often observed: not infrequently, dry skin character is manifested by loss of sweat and sebaceous glands, pathological redness, and abnormal hair and nail growth. If an intact nerve with sensory and autonomic fiber qualities is introduced into the skin area, the dysfunctions can regress. If, on the other hand, the tissue remains denervated over a longer period of time, a so-called "atrophy" occurs, i.e. the corresponding tissue loses volume, cell count and especially functionality. After certain time intervals, the atrophy is irreversible.

In microsurgery, intact neighboring nerves are used to restore the function of lost (denervated) muscles. In most cases, only a small number of replacement nerves are required.

One speaks of a nerve transfer when nerve branches are relocated to denervated muscle nerves or directly to the muscles. If more distant donor veins are to be used for neurotization, they can be "extended" to the target area by an additional removal of nerve transplants (e.g. skin nerves from the lower leg). This is then referred to as neurotization through nerve transplantation. The nerve transplanter or the nerve graft, on the other hand, can in turn be applied to recipient nerves, z. of the denervated target muscle as an "indirect" neurotization or directly into the muscle. If muscle groups in the face are neuroticised to revive facial expression, this is called "facial resuscitation". In this case, the neurotization is used specifically to restore expressiveness.

The duration until the visible or palpable success of the surgical neurotization is different and depends, among other things, on the number of available nerve fibers (axon capacity), blood flow to the donor nerve and the surrounding structures, innervation distance, target tissue and many other factors. Frequently, the neurotization does not start abruptly but gradually and improves continuously up to a point in time of about two to three years after the procedure.

In 1908, Viktor von Hacker (1852 - 1933) performed the first successful direct neurotization in an 11-year-old female patient. During this procedure, he relocated a part of the accessorius nerve (XI cranial nerve) into a muscle in the neck area (trapezius muscle; trapezius muscle).^[2]

Steindler was performed on a dog and Erlacher performed direct neurotization on a dog or a rat in 1915 and found that the formerly denervated muscles could now contract again.^[3] Aitken, who conducted research on rabbits and also sewed nerves directly into the muscles, concluded in 1950 that neurotization also produced new motor end plates.^[4] Contrary to his expectation that only muscles directly around the attached nerve endings could be reactivated, he observed that contractions also occurred in surrounding areas of the muscles. 

In 1969, after further experiments on the dog, Sorbie and Porter came to the conclusion that direct neurotization of the M. flexor carpi radialis (a forearm muscle) could restore the functionality of the muscle in 44% to 95% of cases.^[5] The success rate depended on the time between denervation and neurotization and the number of motor nerve fibers of the implanted nerve. Conversely, the longer a muscle was denervated, the further atrophy progressed until it was finally completely transformed into fatty tissue. The more nerve fibers were present, the higher was the conductivity. In 1970, Scaramella and Smith performed the first facial isanasto-mosis by connecting the hypoglossal nerve (twelfth cranial nerve) with the denervated facial nerve, thereby neurotizing the mimic muscles.^[6] In 1976, Brunelli finally succeeded in demonstrating that after direct neurotization, new motor end plates had also developed in aneural muscle parts, i.e. areas without direct nerve contact.^[7]

A direct connection from nerve to nerve by microsurgery only makes sense in cases of minor damage to both nerve endings, e.g., if the nerve path is cut smoothly and the lesion is short. Neurotization can be performed "end-to-end" (ETE) or "end-to-side" (ETS). In the former, the damaged nerve and a donor nerve are joined together at their ends (usually under the surgical microscope). In the latter case, the distal stump of a damaged nerve is connected laterally to a (donor) nerve (see Fig. 1). A connection of nerves by a nerve suture is also called neurorraphy. ETE apposition seems to be suitable for the so-called "size missmatch", i.e. when the nerves to be connected have different diameters. This is because thicker axons (nerve fibers) are formed at an earlier stage.^[8]

The ETS variant can be used in the primary care of injuries or tumor surgery.^[9] The connection can also be made without a nerve suture using a special adhesive. However, the diameter of the growing nerve fibers will be affected.^[10] In contrast, a 1- and 5-mm window in the outermost nerve sheath promotes nerve regeneration. A disadvantage of ETS nerve attachment is that the different function of the adjacent nerve could affect the target tissue, e.g. muscle activation.

If the gap between the two nerve stumps is too large, a graft is needed to bridge the gap. An example of a nerve transplantation is the cross-face nerve method, in which the facial nerve of the non-affected side is extended into the paralyzed half of the face. Among other things, this procedure involves connecting nerve grafts from the lower legs to nerve branches of denervated muscles. 

In this type of neurotization, a functioning nerve is transferred directly to or into a muscle. For this purpose, the peripheral nerve is separated into as many fascicles as possible using the so-called Brunelli procedure under the surgical microscope.^[11] The individual fascicles are woven into the epimysium (the covering layer between the fascia and the muscle) over a large area of the denervated muscle through separate incisions and fixed in place with fine sutures. The "direct neurotization" (Nerve-to-muscle-neurotization; NTM) can basically be performed on the entire body.^[12] It can also be applied in case of damage at the level of the motor end plate. NTM neurotization can also help in the case of a "size mismatch" by dividing the donor nerve that is too large into two segments.^[13] One segment remains reserved for "direct neurotization", while the other is connected (co-apted) end-to-end to the muscle nerve.

A direct neurotization is successful if motor end plates are formed and the muscle is supplied with electrical impulses again. This allows tonus (basic tension of the muscle cells) and contractility (ability to shorten muscles) to return. If the facial nerve reconstruction does not contain any receiver nerves that can be connected to the facial nerves, but if there are facial muscles that can be reintegrated, they can be directly reanimated using this procedure.^[14]

This technique is contraindicated in the case of long-standing lesions and missing activity signs in electromyography (EMG).

“Nerve-to-skin"-apposition can also occur. In this procedure, an intact nerve with sensory and autonomic qualities is introduced into a denervated skin area. Denervated skin areas can result from traumatic (accidents), surgical, infectious and other causes, such as poor blood circulation, autoimmune diseases or tumor growth. In addition to loss of sensation, a malfunction of the autonomic nervous system is often observed: It is not uncommon for dry skin to manifest itself through loss of sweat and sebaceous glands, pathological redness, abnormal hair and nail growth. This phenomenon can be well observed during operations on the face, such as tightening operations or facial resuscitations.^[15,16] During these operations, the skin of the face is detached from its nervous system, which radiates from the depth of the face, due to the operation. This initially leads to an impairment of sensation in the cheek area for a few weeks until the reinnervation of the sensory nerve (trigeminal nerve) into the skin is gradually completed and skin sensation returns. The nerve-to-skin-neurotization is particularly impressive in face transplants.

In addition, "skin-to-skin-neurotization” is also possible. For this purpose, the skin edges are brought back together again after injuries to the skin, e.g. by sutures, i.e. adapted. In addition to vessels, the finest skin nerves of the innervated skin region also sprouted into the denervated skin area. The sensory perception as well as autonomous nerve qualities regenerate in the formerly denervated skin area.^[17] The autonomic nervous system regulates the function of sweat and sebaceous glands, hair follicles, salivary and lacrimal glands.

In the face, for example, it can be seen that after the surgical approach to reconstruct the facial paralysis with an incision in front of the ear and in the hair-bearing area, the in-nerved skin in the temple area provides the adjacent, initially denervated skin of the cheek with long-lasting feeling again.

Neurotization is also possible from "muscle-to-muscle". This variant is similar to the "nerve-to-muscle method", but here a functional muscle is the source of neuronal supply for a surrounding denervated muscle.  This innervated muscle (usually from the vicinity of the lesion site) thus neurotizes the adjacent denervated muscle. The phenomenon has also been described, for example, in patients with incomplete or early facial paresis by Labbé, in which a temporalis muscle transfer to the midface, the innervated temporalis muscle supplies the (partially) denervated mimic muscles in the midface with new nerve impulses in the sense of a "muscle-to-muscle neurotization".^[18] Observations of muscle-to-muscle neurotization were made by Trojaborg, who documented a phenomenon of "myoneurosis" between the masseteric muscle (one of four masticatory muscles) and the facial mimic muscles as early as 1972.^[19] In 1983, Conley described the neurotizing role of the masseter muscle transposition lobe between the finger-shaped extensions of the lobe and the mimic facial muscles in the sense of muscle-to-muscle-neurotization.^[20]

In the latter case, innervation is performed as in the "muscle-to-muscle" variant, but with the addition of an intermediate nerve graft (nerve interposition).

Furthermore, Taupin and Labbé observed a "muscle-to-nerve"-neurotization.^[21] For example, in a patient whose facial nerve had been damaged during surgery on the parotid gland (Glandula parotideus), insertion of the facial nerve into the masticatory muscle (M. massetericus) resulted in regained mimic expression and improved resting tension (resting tone).

Finally, the necessity of timely decisions and, if necessary, therapies should be pointed out. Continued denervation and lack of re-innervation leads to a deterioration in the blood and nutrient supply of the affected muscles as well as the ability to synaptogenesis, i.e. the formation of switch points between cells.^[22,23] The function of the muscle can be permanently impaired or even completely lost. Therefore, according to the "time-is-muscle" principle, if there are indications of a lack of reinnervation and consequently a lack of timely recovery of muscle function, or if the facial nerve is not able to continue to function due to anatomical reasons (e.g. after tumor resection including segmental parts of the facial nerve or its sub-branches), the indication for neurotization by microsurgical surgery should be established early on.