Nerve Transfers in the Treatment of Peripheral Nerve Injuries

Successful re-innervation of proximal limb peripheral nerve injuries is rare. Axons regenerate at ~1 mm/day, reaching hand muscles by 24 months, finding them atrophied and fibrosed. Peripheral nerve injury repair is often delayed waiting for spontaneous recovery. This waiting time should not be longer than 6 months as after 18 months rein - nervation will not achieve effective muscular function. When spontaneous recovery is impossible, referral too late or damage too severe, other options like a transfer from a nearby healthy nerve to the injured one must be considered. They are very successful, and the deficit in the donor site is usually minimal. The most common nerve transfers are a branch of the spinal nerve to the trapezius muscle to the suprascapular nerve, a branch of the long head of the triceps to the axillary nerve, a fascicle of the ulnar nerve to the motor branch of the biceps muscle, two branches of the median nerve to the pos terior interosseous nerve and the anterior interosseous nerve to the ulnar nerve. There are many more options that can suit particular cases. Introduced in brachial plexus injury repair, they are now also applied to lower limb, to stroke and to some spinal cord injuries.


Introduction
Peripheral nerve injuries can represent a serious problem, particularly when involving the brachial plexus. They usually induce devastating consequences and affect young people [1]. The main cause is traffic accidents.
Motor endplate degeneration starts just after a motor nerve is injured. The growth speed of the regenerating axons is ~1 mm/day [2]. The time needed for the regeneration will be proportional the distance between the injury site and the muscle endplates [3,4]. Proximal limb peripheral nerve injuries pose severe difficulties to a successful re-innervation because of the long distance regenerating axons have to cover [3], taking up to 24 months to reach hands or feet [2,5,6], often finding them atrophied and substituted by fat and fibrous tissue [7][8][9].
Peripheral nerve injury repair is often delayed waiting for spontaneous recovery. This waiting time should be no longer than 6 months [10] as after 18 months successful re-innervation will not achieve effective muscular function [11][12][13][14].
Nerve grafts are often required [15,16]. Unfortunately, their use is associated with worse results than direct repair [17], particularly in grafts longer than 7.2 cm [1,18]. This occurs because the regenerating nerve fibres must cross two anastomoses instead of just one. The second anastomose site is reached much later with more fibrosis hindering the nerve fibre growth to cross it [19]. Another reason for this is that only autologous sensory nerves are used as grafts to minimize donor site deficits [20]. It has been shown that using sensory nerve grafts to repair motor nerve defects is associated with worse regeneration results than if motor nerves are repaired with motor nerve grafts [21]. Direct repair is not always possible: when there is no chance of spontaneous recovery (i.e. root avulsion), the referral is too late, the damage is too severe, the scarring at the injury site is significant, presence of large neuromas in continuity or in multilevel nerve injuries [22]. In these cases, a nerve transfer from a nearby healthy nerve is a superior option. A healthy nerve is transected and coapted to a nearby injured one. This transforms a proximal nerve injury into a distal one near the motor endplates, reducing the time required for re-innervation [10,13]. Unfortunately, the functional improvement is at the expense of reducing the number of functioning nerves [23]. Obviously, the function lost must be less essential than the one we expect to recover [24]. They yield better results than direct nerve repairs, particularly in proximal limb injuries and when a nerve graft is needed [9,25,26]. With good surgical planning the deficits induced on transecting the donor nerve are minimal [13,24].
Distal nerve transfers in proximal nerve injuries reduce the time muscles are denervated, thus improving the outcomes [24,27]. Nevertheless, the best results are obtained with simultaneous proximal nerve injury repair and distal nerve transfers [9] as this combination re-innervates more muscles [9].
Nerve transfers offer better results than tendon transfers [28]. They preserve the original anatomical situation of muscles and tendons, allowing a much better physiological function [11,12,14,22,29,30]. Moreover, nerve transfers can re-innervate more than one muscle and thus Co-contraction: it can be useful in the case of synergistic action between donor and recipient muscles. This is the case in the SAN to SSN transfer as the trapezius is synergistic with the supraspinatus and infraspinatus action. In most other cases it is an inconvenience [22,24,43,44]. For example, in the Oberlin procedure (a fascicle of the ulnar nerve (UN) is transferred to the biceps muscle (BM) nerve branch), there is a tendency for finger flexion when attempting elbow flexion [45]. This is also the case of medial pectoral nerve (MPN) to musculocutaneous nerve (MCN) transfer in which elbow flexion is associated with shoulder adduction [45]. A more dramatic example is phrenic nerve (PHN) to radial nerve (RAN) transfer as patients must take a deep breath before attempting hand extension [44,46]. In some cases, it is so serious that it can make the procedure useless (i.e. contralateral C 7 nerve root transfer) [43].
Previous damage to the donor nerve: it is always a possibility as muscle weakness is only clinically evident when at least 50% of the motor axons are lost [45]. It may explain the variability in the clinical outcomes [45,47].
An adequate post-operative rehabilitation is a vital element in the final outcome and relies on cerebral plasticity in which neurons are assigned to new tasks [4,48].
Initially, motor nerve transfers were the main concern. Over time it became obvious that sensory recovery is also essential as it allows a better motor control and avoids trophic ulcers [49][50][51][52]. This leads to the introduction of sensory nerve transfers [50,52].
Nerve transfers were first used in the upper limbs but with time have also been applied to the lower limbs.

History
Balance in 1903 was the first to report a nerve transfer (SAN to facial nerve) [53] but it was Tuttle in 1913 the first to use them to repair brachial plexus injuries [54]. Vulpius and Stoffel [55] in 1920 described the use of the MPN as donor nerve [56]. Harris in 1921 reported the RAN to median nerve (MN) transfer [57]. Förster [58] in 1929 transferred the thoracodorsal (TDN) and subscapular nerves to the axillary nerve (AXN). Lurje in 1948 transferred the pectoral and TDN nerves to the MCN [59]. Seddon in 1963 described the use of the intercostal nerves (ICNs) as donor nerves [16]. Samardzic et al. in 1980 performed the first double nerve transfer, pectoral to AXN and TDN to MCN [60]. Bedeschi et al. in 1984 introduced the sensory nerve transfers [61]. Novak and Mackinnon in 1991 reported the pronator quadratus (PQ) to UN motor fascicle transfer in proximal ulnar nerve lesions [62]. Brandt and Mackinnon [63] in 1993 reported their experience with pectoral to MCN transfer and Oberlin et al. [64] in 1994 reported the UN to biceps muscle nerve (BMN) transfer. Ever since, many nerve transfers have been reported. Experience has settled the indications and outcomes of each of them. Mastering all of them allows adaptation to all circumstances as the ideal donor is not always available.

Types of nerve transfers
Attending to the nerves involved they can be classified as motor or sensory. The motor transfers aim to recover movement and to avoid subluxation (common in a denervated shoulder) [24].
The sensory transfers aim to recover, at least, protective sensation, avoiding skin ulcerations [52]. The sensory recovery, even if partial, will help with neuropathic pain control [12,65].
End-to-end anastomosis: The distal stump of the donor nerve is coapted with the proximal stump of the recipient one. It is the best option for all nerve transfers, and the only successful one in motor restoration [66].
End-to-side anastomosis: The proximal end of an injured nerve is coapted to the side of a healthy one after creating an epineurial window in it [67]. The idea is that the axons of the healthy nerve create lateral sprouts that grow inside the damaged one. Although axons can travel in the epineurial space of rabbit nerves [18], in humans the epineurial window is essential to achieve axonal regeneration [68]. Sensory axons will spontaneously sprout from the healthy into the injured nerve, providing a kind of protective sensation, although it is never fully normal [11,65,66]. Meanwhile, donor nerve motor axons need an injury (crush or axotomy) to sprout inside an end-to-side coapted damaged nerve [66,69]. It can be useful for sensory nerves but not for motor ones.
Reverse end-to-side or 'supercharge' end-to-side anastomosis: A healthy nerve is transected and coapted to the side of a damaged one [70]. The idea is that the axons of the healthy nerve grow inside the injured one. It provides a fast muscle re-innervation with preservation of the muscle bulk until the axons of the damaged nerve regenerate and reach their own endplates [66]. This avoids muscle atrophy while the injured nerve axons regenerate [71]. It has been used successfully in the case of anterior interosseous nerve (AIN) to motor fascicle of the UN transfer [52].
Single nerve transfer is when only one transfer is performed. Dual nerve transfer relates to the use of two different transfers to achieve the same function (i.e. shoulder abduction, elbow flexion, etc.).
In a direct nerve transfer donor and recipient nerves are coapted directly with no graft interposed. A tension-free suture is essential for a successful recovery [30].
In tetraplegic patients, the most common nerve transfers are: teres minor nerve (TMN) to TLH nerve to recover elbow extension, supinator nerves (SNs) to PIN for hand and finger extension, ECRB to flexor pollicis longus nerve (FPLN) to recover thumb and index finger flexion and brachialis nerve branch (BCN) to AIN for thumb, index and middle finger flexion.

Scapular nerve transfers
Long thoracic nerve (LTN) damage is associated with scapular winging. To correct it one of the two branches of the thoracodorsal nerve (TDN) can be coapted with the LTN [72] (Figure 1). The re-innervation of the serratus anterior muscle (SAM) improves shoulder function [73].

Shoulder nerve transfers
Recovery of shoulder function is the second priority in brachial plexus injury. Shoulder abduction can be recovered with the double nerve transfer SAN branch for the trapezius to SSN together with TLH nerve to the AXN [45]. This dual shoulder transfers offer much better results than just one of them [17,30].
In the SAN to SSN transfer, the distal branch of the SAN destined to the lower part of the trapezius muscle is transferred to the SSN, leaving the superior branches intact [38]. Results are much better with no nerve grafts interposed [17,74]. As distal injury to the SSN can be present in addition to a more proximal brachial plexus damage, some recommend to dissect the SAN as distally as possible and to make the coaptation with the SSN as close as possible to the suprascapular notch [75,76]. This transfer can be performed through an anterior or a posterior approach (Figures 2 and 3). In some, the posterior approach is better, as a smaller part of the trapezius muscle is denervated [77,78]. Others disagree because it is technically difficult and because it cannot be done through a regular brachial plexus exploration [76], lengthening the surgical procedure [75]. The SAN should be used as a donor with caution if the serratus anterior muscle (SAM) is also paralysed for the risk of scapular winging [45].
First described by Lurje [79] in 1948, the RAN to AXN transfer was popularized by Leechavengvongs et al. [80] in 2003. There is no agreement on which is the best RAN branch to use [14,38,80]. Some surgeons report that, it is the TLH branch because it contains more motor axons, being the medial branch its alternative [81], but others think the opposite because as the TLH muscle inserts in the scapula it is part of the scapulohumeral joint [24] and because the medial head is longer and easier to isolate [82]. The results in shoulder abduction are good, particularly if combined with an SAN to SSN transfer [17,38,80]. As the recovery of shoulder external rotation is unsatisfactory [75,83], many recommend to include the TMN in the transfer [38,77,80,84]. The TLH to AXN transfer can be done through posterior to anterior approaches (Figures 4 and 5). The first one is the most widespread [85,86], but the second is ideal if an Oberlin procedure is planned [87]. Both approaches show similar clinical outcomes [85,87].

Elbow flexion nerve transfers
This is the priority in brachial plexus injuries. First reported in 1994 [64], the Oberlin procedure is the transfer of the UN fascicle for the flexor carpi ulnaris (FCU) to the biceps muscle nerve (BMN) branch. To improve the results, some recommended a double nerve transfer adding the   (Figure 6). This double transfer technique has lost popularity after two studies showed no difference in clinical outcome when compared with the Oberlin procedure [103,104]. This procedure yields the best results provided the patient has a strong hand. Otherwise other alternatives must be considered.

ICN to MCN transfer:
Two to three intercostal nerves should be transferred. The results are only fair, but can be the only choice in five root brachial plexus avulsion [105][106][107].
MPN to MCN transfer: Indicated in C 5 -C 6 or C 5 -C 6 -C 7 nerve root injury with preservation of pectoralis muscle (PM) function [45]. This muscle is innervated by the superior, medial and lateral pectoral nerves, allowing it to retain some function when one of its branches is used as a donor [108] (Figure 7). It provides acceptable results [45,63], but often a nerve graft is needed. This impairs the clinical outcome [109].

TDN to MCN transfer:
Recommended if the Oberlin procedure is not possible [110,111]. Not advised in the case of a weak shoulder adduction or if a muscle transfer is planned.  Peripheral Nerve Regeneration -From Surgery to New Therapeutic Approaches Including Biomaterials and Cell-Based Therapies Development Other options: SAN to MCN [112,113] and PHN to MCN [114]. Both usually need a nerve graft. None of them yield such good results as to recommend it [10].

Elbow extension nerve transfers
Although aided by gravity, there are many daily life activities that require active elbow extension (reaching overhead objects, changing from sitting to standing position, working over a table, throwing objects, changing from chair to bed in SCI patients, etc.) [115]. Restoration of elbow extension is particularly important in tetraplegia. The recipient nerve is usually the nerve branch for the TLH. The best results have been obtained by transferring the TMN to the TLH [116,117]. Other possibilities are to re-innervate the TLH with ICNs [24,92,118,119], a UN fascicle [24], the MPN [120], TDN [111], PHN [121], contralateral C 7 nerve root [122] and an RAN fascicle for the hand [123]. The results have been poor, particularly the ICNs [119].

Intercostal nerve transfers
First used by Seddon [16] in 1963 in brachial plexus repair. Only recommended when there is no other choice (i.e. C 5 -T 1 brachial plexus avulsion). Harvesting them is technically demanding, requiring arterial hypotension to control the bleeding as the cautery cannot be used until the ICN is fully harvested [24]. Up to seven ICNs can be transferred. The first one was used by Durand et al. [91] in a single case. Harvesting the second one is not advised as it provides a large sensory contribution to the arm [24] (Figure 8). Additionally, it is technically very  difficult to harvest and a nerve graft is always needed [24]. Usually, the third to the fifth intercostal nerves are the ones used. In women, the fourth one should be preserved to retain the nipple's area sensation. After harvesting the mean available, ICN length is 11-12 cm [124], so no nerve graft is usually needed. At least two of them per recipient nerve are needed [24,124]. They have been used to re-innervate many nerves, like the AXN [89,92], MCN [24,105,106,[124][125][126], TLH [92,118,119], TDN [89,127] and SSN [90,91]. Their sensory branches can be used to recover some limb sensation, ameliorating the neuropathic pain. Unfortunately, not being synergistic with the recipients nerves a long re-education must be expected [118]. Usually their harvest is not associated with any pulmonary dysfunction [24,128].

Phrenic nerve transfers
It has been used in C 5 -T 1 nerve root brachial plexus avulsion to re-innervate the MCN [106], the median nerve (MN) [129] or the RAN [46]. Unless its whole intra-thoracic segment is harvested, a nerve graft is needed [129]. The clinical results are acceptable provided there is no other choice. Patients usually need to take a breath before starting the movement with the re-innervated muscle. Post-operatively patients show a decreased pulmonary capacity that improves after 2 years [114,130]. It is not commonly used these days.

Contralateral C 7 nerve transfer
It has been used in complete brachial plexus avulsions. It requires a long nerve graft or to shorten the humerus [122,131], but this can be avoided crossing the donor C 7 nerve root through the C 6 -C 7 disc space [132]. The targets are usually MN or MCN. Its use has been discouraged as its clinical results are poor and unreliable, the forearm and hand muscles do not get a good re-innervation and there is co-contraction of the donor and recipient limbs [24,43]. In fact, initiating the movement often requires to start it in the contralateral normal side and there is co-contraction of the muscles of the donor and recipient sides [24]. Its value is very much disputed.

Wrist and finger extension
In the case of proximal RAN damage with an intact MN, the best choice is the dual nerve transfer described by Mackinnon et al. in 2007 [133]. The FDS branches (usually there are two) are coapted to the ECRB branch to recover wrist extension [134] and the branches for the FCR and palmaris longus (PL) are coapted with the PIN to recover finger extension [32,50,135] (Figure 9). This combination provides the best outcome as muscles are synergistic [29]. Contrariwise to tendon transfers, this dual nerve transfer recovers independent finger extension [11,32,135].
Bertelli and Ghizoni reported successful restoration of wrist extension transferring the PQ motor branch to the ECRB [136] (Figure 10). This technique is very useful but is more technically demanding than the previous one.
The pronator teres (PT) branch is not recommended as a donor for RAN re-innervation because pronation is essential for many daily living activities and because this muscle can be used for a tendon transfer in case the nerve transfer is unsuccessful [31,135].
Peripheral Nerve Regeneration -From Surgery to New Therapeutic Approaches Including Biomaterials and Cell-Based Therapies Development   In C 7 -T 1 brachial plexus injuries, the shoulder and elbow mobility is preserved, but the finger movements are lost. The supinator muscle (SM) innervation is preserved as is comes from the C 6 nerve root. Thus, it is possible to coapt one or both SN branches to the PIN (Figure 11). This helps to recover the function of the extensor pollicis longus (EPL) and extensor digitorum communis (EDC) muscles. It is a very successful nerve transfer [137][138][139].

Finger flexion and median nerve hand function
The primary goal of MN recovery is to provide first and second finger pincer as well as thumb opposition [29].
Reported by Palazzi et al. [140] in 2006 the BCN to AIN nerve transfer is indicated in the case of C 8 -T 1 nerve root or lower brachial plexus injury with a MN dysfunction. It provides improvement in hand function [13,[141][142][143] but there are other transfers with better clinical results. It is recommended only if the MCN nerve is intact.
García-López et al. [144] reported a single case of brachioradialis muscle (BRM) nerve to AIN nerve transfer with return of finger flexion.
Thenar muscle re-innervation can be achieved coapting the AIN terminal branch to the PQ with the MN motor thenar branch [145]. A nerve graft is usually required [29] but it is a very effective procedure [29,145,146].
The FDS, FCR and FCU branches can all be transferred to recover AIN function [147]. Finger flexion, particularly the thumb and index finger, can be recovered by coapting the nerve branch for the ECRB to the AIN [29]. One or both SM branches can be coapted with the AIN to recover FPL and FDP function [142]. Some have transferred both the ECRB and SM branches to the AIN to recover finger flexion [148]. The results of these techniques are very encouraging [149].

Pronation recovery
To restore active pronation, essential in many daily living activities, some have transferred the FCU nerve branch to the PT nerve [150]. Others have transferred one of the branches of the FDS to the PT nerve [40]. More recently, the nerve for the ECRB has been transferred to the PT branch [142]. This last technique has a widespread acceptance.

Ulnar nerve hand function
When the UN is damaged in the arm or more proximally, the recovery of hand intrinsic muscles is dismal [151]. The motor recovery can be improved by coapting the AIN terminal branch for the PQ to the motor fascicle of the UN [50,62,146,152,153] (Figure 12). This technique was originally described in 1997 by Wang and Zhu [146]. If this fascicle is neurolised proximally enough in the forearm, no nerve graft is needed [29]. The clinical outcome is very satisfactory [29,62,152]. Another possibility is a reverse end-to-side transfer, avoiding atrophy of the UN innervated hand muscles while awaiting for the native UN motor axons to regenerate [70,71,154]. It is very effective [29].  Transfer of the terminal branches of the extensor digiti minimi (EDM) and the extensor carpi ulnaris (ECU) to the UN motor branch in the forearm has been reported. In this single case, a 10-cm nerve graft had to be used and the recovery was fair [155]. It is not recommended unless there is no other option.

Nerve transfers for upper limb sensation recovery
Sensory nerve transfers sacrifice nerves that serve areas with non-critical sensation to recover it where this sense is vital (i.e. tip of the thumb and index fingers) [33,49,51,61,65]. They also help with neuropathic pain control [13,29,49,156]. The donor nerve distal stump can be coapted end-to-side to a nearby sensory nerve to regain some protective sensation [14,31,66].
In the case of proximal MN damage, restoring the sensation in the ulnar aspect of the thumb and the radial side of the index finger is a priority to allow a useful pincer mechanism [29]. The donors are the nerves supplying less essential areas like the third web space (MN branch) the forth web space (UN branch), the dorsal sensory branch of the UN and the radial sensory nerve (RSN) [22,29,49,50,65,157,158]. Ducic et al. [159] in 2006 recovered the sensation of the thumb and index fingers using the radial nerve branches as donors. Bertelli and Ghizoni [158] in 2011 reported the transfer of the distal superficial radial finger nerves of the thumb and index fingers to the ulnar aspect of the thumb and the radial aspect of the index finger. Flores et al. [52] transferred the superficial ulnar nerve to the third palmar digital nerve.
In the case of proximal RAN damage, the sensation in the dorsum of the hand can be recovered by coapting the lateral antebrachial cutaneous nerve (LABCN) to the RSN [148] (Figure 13). At Peripheral Nerve Regeneration -From Surgery to New Therapeutic Approaches Including Biomaterials and Cell-Based Therapies Development the outer aspect of the elbow, both nerves run parallel to each other. The LABCN goes with the superficial radial vein and the RSN with the deep radial vessels. The LABCN is sectioned as distally as possible and coapted to the proximal part of the RSN [17].
Protective sensation in the hand ulnar innervated areas can be recovered with a sensory nerve transfer from the third web space (MN branch) [29] or from the RSN [160].
In C 7 -T 1 nerve root injuries the LABCN can be coapted with the sensory fascicles of the UN in the forearm to recover the sensation in the hand [12].

Nerve transfers in the lower extremity
Three areas have been explored. At the proximal level, nerve transfers between the femoral (FN) and obturator (OBN) nerves; at the knee, the nerve transfers between branches of the posterior tibial nerve (PTN) and the peroneal nerve (PN); and at the foot, some sensory nerve transfers for recovery of protective sensation. There have been some attempts to recover urinary continence in spinal injured patients.
FN injuries are the most disabling as they impair the capacity of standing and walking. The anterior branch of the OBN has been successful in re-innervating the FN [119,161,162]. The anterior branch of the OBN is selected to preserve the primary leg adductor muscle [162]. The reverse transfer using an FN motor branch as donor to coapt it to the OBN has also been used with successful clinical outcomes [163].
PTN to PN transfer to recover foot dorsiflexion has been attempted [164][165][166] but the reported outcomes are inferior to the posterior tibial tendon transfer [167].
Nerve transfer from an FN branch to the pudendal nerve to recover urinary continence has been achieved in a canine neurogenic bladder model [168] but its clinical application in the human being is still pending.

Transfers for spinal cord injured patients
Around a 50% of the SCI involves the cervical spinal cord [30]. Tetraplegic patients suffer from a variable loss of arm and hand functions, usually asymmetrical [30]. This creates serious difficulties to perform their daily activities (transfers back and forth from the wheelchair, feeding, computer handling, self-catheterization, etc.) [169]. To recover any partial arm and/ or hand function might mean an immense impact on their quality of life [170].
Nerve transfers used in SCI patients aim to recover elbow, wrist and finger extension, palmar grasp and thumb and index finger pinch and release. The nerve transfers mentioned above can also be used in these cases. The only difference is that in SCI there are three spinal cord areas [170][171][172]. The area above the injury will have normal spinal cord and nerves; the area of the injury will have neuronal loss and severe muscle atrophy. To recover function in this area, nerve transfers must be planned no later than 1 year after injury.
Below is the area of normal spinal cord disconnected from the rest of the central nervous system. The muscles depending from this area are not denervated, so nerve transfers can be done any time. The first area is the donor and second and third areas are the recipients. We aim to recover some functions of areas 2 and 3 transferring some nerve branches from area 1.
In SCI, it is recommended to wait 12 months to give a chance for spontaneous recovery [172].
Elbow extension has been achieved by transferring the TM motor branch to the TLH [116].
Wrist and finger extension can be recovered with SN to PIN transfer [173,174].
Thumb and index finger pinch is restored transferring the ECRB motor branch to the AIN [175,176].
The BCM branch has been transferred to the AIN fascicle in the arm to recover FPL and FDP function [147,177,178].

Conclusions
Nerve transfers have become an essential way to repair irrecoverable peripheral nerve injuries. Mastering these techniques is essential for the peripheral nerve surgeon. The best results are obtained when patients are young; the procedure is not delayed more than 6 months after the injury, donor and recipient nerves are agonistic and when the donor nerve has no damage. Shoulder and elbow motor recovery is very successful in most patients. Hand recovery can also be achieved but results are not so good. The biggest experience is in upper limb nerve transfers. Lower limb nerve transfers have been attempted but the experience is limited and the choices few. In tetraplegic patients, we aim to recover some of the lost functions, simplifying their daily lives. Peripheral Nerve Regeneration -From Surgery to New Therapeutic Approaches Including Biomaterials and Cell-Based Therapies Development