Open access peer-reviewed chapter

Nerve Root Reimplantation in Brachial Plexus Injuries

Written By

Vicente Vanaclocha-Vanaclocha, Nieves Saiz-Sapena, José María Ortiz-Criado and Leyre Vanaclocha

Reviewed: 06 November 2018 Published: 08 April 2019

DOI: 10.5772/intechopen.82431

From the Edited Volume

Treatment of Brachial Plexus Injuries

Edited by Vicente Vanaclocha and Nieves Sáiz-Sapena

Chapter metrics overview

1,260 Chapter Downloads

View Full Metrics


Nerve root avulsion is the most severe form of brachial or lumbosacral plexus injury. Spontaneous recovery is extremely rare, and when all the nerve roots of the affected plexus are avulsed, the therapeutic options are very limited. Nerve root reimplantation has been attempted since the 1990s, first in experimental animal models and afterwards in human beings. Currently, only partial recovery of the proximal limb muscles has been achieved. New therapeutic strategies have been developed to improve motor neuron survival and axonal regeneration, with promising results. Neurotrophic factors and some drugs have been used successfully to improve the regenerating ability, but long-term studies in humans are needed to develop complete recovery of the affected limb.


  • brachial plexus injury
  • nerve root avulsion
  • nerve root reimplantation
  • motor neuron death
  • muscle atrophy
  • neurotrophic factor
  • axonal regeneration
  • motor and sensory recovery

1. Introduction

A common event in brachial plexus (BP) injury is nerve root avulsion (NRA) in which the nerve rootlets (NRts) are torn from the spinal cord (SC) [1, 2, 3]. Once avulsed, the NRts retract towards the nerve root (NR) sleeve [4]. The most common cause is traumatic NR stretching due to road accidents or parturitions [3, 5]. These injuries can also happen but are much rarer at the lumbosacral plexus [6]. The ventral rootlets (motor) are weaker and thus get injured more often and more seriously than their posterior counterparts [7].

Soon after avulsion anterior horn motor neurons (MN) and sensory neurons at the dorsal root ganglion (DRG) undergo apoptosis [8, 9, 10, 11, 12, 13, 14, 15, 16, 17]. Inside the avulsed NR itself, there is a Wallerian degeneration with axonal and myelin loss [18]. The muscles, devoid of nervous impulses, undergo atrophy and fibrous transformation [19, 20]. At the SC, the neurons suffer loss of synapses with destruction of previous neuronal networks and creation of new anomalous ones that will lead to abnormal nerve impulses which might induce chronic neuropathic pain [21, 22, 23, 24].

After complete NRA, spontaneous regeneration is impossible [9]. In case of a single NRA, recovery coming from nearby healthy ones can be expected in neonates but not in adult patients [25]. Ventral root surgical reimplantation has been attempted both in experimental animals and in human beings with partial recovery [26, 27].

Axonal regeneration is stronger in direct ventral NR reimplantation [26, 28]. This is rarely possible [4, 7, 29, 30], so peripheral nerve grafts (NGs) are used to cover the gap between the SC and the remains of the avulsed NR [31, 32, 33]. These NGs are usually taken from a peripheral sensory nerve (medial antebrachial cutaneous, radial cutaneous, and saphenous), which is not the ideal situation as motor nerve regeneration is worse if sensory nerves are used as donors compared to mixed or pure motor nerves [34, 35, 36]. Acellular conduits have also been used, but the regeneration does not grow further than 2 cm [37, 38].

1.1. Historical background

Surgical repair of spinal NRs after traumatic avulsion in live human beings was considered technically impossible until the pioneering work of Carlstedt et al. [39]. The first studies were done in rats [40], then in cats [41] and finally in primates [42, 43], before attempting NR reimplantation in humans [44]. Initially, the efforts were directed at repairing the ventral rootlets (motor), but in adult human beings, it provided only mild improvement in shoulder and elbow movements [45]. In children, some hand movement was recovered but with limited function [29]. In addition, it was found that the number of surviving MNs and the number of axons that regenerated after NR reimplantation had a direct relationship with the final functional recovery [7, 30]. Ever since, many research groups have focussed on understanding the underlying pathophysiology and to find surgical strategies and drugs that can enhance regenerating capacities.


2. Pathophysiology

The interface between the central and peripheral nervous systems is known as the transitional zone (TZ) [46], and the regenerating capacities are influenced by both of them. The first is rich in astrocytes that create channels through which motor fibers pass [15]. The latter has Schwann cells that secrete neurotrophic factors (NFs) with higher regeneration abilities [47].

NRA disconnects the transverse arch that exists at each spinal level between the posterior horn sensory, the lateral horn autonomic and anterior horn neurons [23] as well as disconnection of the DRG neurons from the bulbar and thalamic sensory nuclei [48]. NRA also induces loss of synapses and dendritic arborisation, fiber degeneration, neuronal death, posterior spinal column degeneration and glial proliferation [23, 48]. The synaptic and neuronal changes in the posterior horn produce neuropathic pain [24, 48, 49].

NRA is followed by an intense inflammatory SC reaction [50] with microglia, macrophage and glial proliferations [51]. At the TZ a dense scar tissue and a neuroma from the avulsed MN develop [15, 46, 52, 53, 54, 55]. In the normal situation, the central nervous system is rich in astrocytes that create channels through which the nerve fibers pass [15]. After NRA, astrocytes proliferate and rearrange, blocking those channels and making it difficult for the regenerating nerve fibers to grow [15, 46, 56]. Axonal and dendrite regeneration is inhibited by the secretion of some substances by the astrocytes (chondroitin sulphate proteoglycans or CSPGs) [57, 58, 59] and oligodendrocytes (myelin protein [60, 61, 62] and semaphorin-3 [63]). Additionally, the glia secrete neurotoxic products like glutamate [15] and free radicals [64] that induce massive neuronal death among motor [8], sympathetic [12], parasympathetic [12] and posterior horn sensory neurons [17].

About 80% of the MNs die in the following weeks [13, 65, 66], but this death does not happen immediately after NRA [13, 67, 68]. Instead, there is a 12-day period in which different treatment strategies can reduce this MN loss [65, 69]. The chemical compounds that counteract the glutamate toxic effects can reduce the MN loss by 70%, provided that they are administered in the first 2 weeks after the NRA [16, 65, 69].

The closer the axonal injury to the neuronal body [55], the smaller the regenerating capacity of the axon and the higher the chance that the neuron will die. Four millimeters is the minimum amount of peripheral nerve that should remain to avoid MN death [70].

The surviving MNs develop axonal sprouts within 1 month after the NRA [41], but to achieve a successful regeneration, the axons must cross the gliotic TZ, grow inside the distal peripheral nerves, and reach the motor end plates [71]. The long distance to cover is a big impediment to a successful functional recovery [72, 73]. By the time the muscles get reinnervated, they are atrophic and with fibrotic changes, particularly the most distal ones [74]. The regeneration is not privative to the axon, and the dendrites can also regenerate as axon, creating what has been called a dendraxon. These also have the capacity to grow into the peripheral nerves and reinnervate muscles [75, 76].

Although the MN regenerating axon has a chance to cross the anterior SC white matter to reach its surface and then attempt to grow in a possible reimplanted NR [77, 78] for the DRG growing axon, the same is almost impossible as they have to cross a very hostile and gliotic posterior SC Dorsal Root Entry Zone (DREZ) [79, 80, 81].

In the human being, the avulsion damages more frequently the ventral NRts as they are more fragile than their posterior counterparts [15].

NRA creates four problems that have to be addressed to achieve a successful repair. First, if the axon is torn closer than 4 mm to the cell body, motor and preganglionic parasympathetic neurons undergo apoptosis [10, 11, 12, 13, 23, 67, 68, 70, 82, 83, 84]. Second, muscles are fibrotic by the time the regenerating axonal sprouts reach the motor end plates [72, 73]. In rats, functional recovery is seen only in cervical but not in lumbosacral avulsion models as the distance to cover is much shorter for the cervical NRs [9, 40, 85, 86, 87], and in any case only proximal limb muscle recovery is seen [86, 87, 88, 89]. Third, the regenerating fibers may reach the wrong target due to misrouting [53], and in the absence of NG or conduit, the regenerating axons will grow along the surface of the SC [27, 43, 53, 83, 87]. The misrouting is responsible for simultaneous contractures in agonist and antagonist muscles leading to ineffective limb movements [30]. Fourth, there is severe muscular atrophy due to lack of use [74]. Hence, for a successful clinical result, MN survival must be improved, axonal regeneration has to be enhanced and accelerated, misrouting should be minimized and muscle atrophy should be prevented [15, 72].

Although the MN cell body can regenerate and grow a new axon after this is torn [69, 90], many MNs apoptose [13, 65, 69], and only 80% of the surviving MNs do finally project a regenerating axon in the reimplanted ventral root or NG [26, 27, 31, 86]. Reimplantation of avulsed NRs either directly or by means of a peripheral NG helps to reduce the number of MNs undergoing apoptosis, probably because of local NF production [69, 77, 89, 91, 92, 93]. Exogenous NFs can be administered to enhance the regenerating capacity of cells [47, 94, 95].

Historically, the first attempts were directed at motor recovery with ventral rootlet reimplantantion [96], but recently sensory recovery has been proved possible by reimplanting dorsal rootlets [97]. The results of dorsal rootlet repair are dismal because the SC glial proliferation creates barriers that prevent the regenerating DRG axons from reaching the posterior SC horn [81]. The lack of sensory recovery induces chronic neuropathic pain [49, 98], and the lack of proprioception causes limb clumsiness [30]. This has been partially avoided by direct implantation of the dorsal rootlets or their NGs’ extensions inside the posterior horn itself rather than on the surface of the SC [81, 99]. The repair of both motor and sensory NRts leads to better functional results with more accurate movements and less muscular synkinesis [100]. Functional MRI studies have corroborated affected limb sensory cortex function recovery in the area corresponding to the reimplanted NR [100].

The timing of NR reimplantation is crucial, as a longer waiting period will correlate with a greater amount of MNs undergoing apoptosis [20, 27, 91, 93, 101, 102, 103]. The percentage of dead MNs increases from 20% by 10–12 days post-avulsion [13, 65, 69] to 50% by 4 weeks [104, 105], 85% by 6 weeks [106] and 90% by 20 weeks [27, 83, 93, 107]. Early NR reimplantation seems to have neuroprotective effects [27, 83, 89, 93, 108, 109], but some MN loss will happen even if repair occurs immediately after avulsion [93, 101]. In animal models, NRA followed by immediate reimplantation in the same surgical procedure minimizes MN apoptosis and achieves muscle reinnervation with some limited functional recovery, which is better in the brachial plexus than in the lumbosacral plexus [27, 69, 83, 110]. Ideally, the surgical repair must be performed no later than 10 days post-injury [65] as a delay over 2 weeks will lead to poor clinical results [20, 26, 27]. In clinical practice, patients suffering from brachial or lumbosacral plexus avulsions often experience other concomitant injuries, sometimes quite serious, that force delaying NR repair [111]. Another common scenario is that the precise diagnosis takes weeks or even months [3]. In any case, in human beings NRA repair has to occur no later than 1 month after the injury to allow any motor function recovery [45, 74, 97, 100]. NGs are almost always needed as torn NRts retract and undergo fibrosis with time, making direct reimplantation to the SC impossible unless the repair is done just a few days after the injury [74]. This is a further difficulty as regeneration is worse with NGs than with direct NRt reimplantation [26].


3. Pharmacological aids to enhance regeneration after nerve root reimplantation

Several pharmacological aids have been introduced to improve MN survival and axonal regeneration after anterior spinal NRt reimplantation. They can be classified into NFs, drugs and cell-derived products (Table 1).

Agent Group Mechanism of action Administration route Motoneuron survival post-injury Axonal regeneration Observation Applied to Current human clinical use
Brain-derived-neurotrophic-factor (BDNF) NF Reverses cholinergic transmitter-related enzyme deficiency Intrathecal Motoneuron survival 53% by 16 weeks Abundant regenerating fibers reaching cord-avulsed root interface Active against many neurodegenerative disorders Rat None
Glial-derived-neurotrophic-factor (GDNF) NF ⇑ Survival of dopaminergic neurons Direct administration on spinal cord Completely prevents motoneuron loss at 16 weeks post-avulsion ⇑ Axonal regeneration and coiling and regeneration Schwann cells Strongest NF. ⇑ Effect combined with Riluzole
Administration before 2 week post-avulsion
Rat None
Ciliary NF (CNTF) NF Activates motor neuron signal transducer and transcription 3 activator(STAT3) Direct administration on spinal cord Motoneuron survival 23 ± 4.3% by 3 weeks post-avulsion ⇑ Axon regeneration across interface spinal cord/nerve root Conjugation it with transferrin prolongs its action Rabbit None
Intracellular sigma peptide (ISP) NF ⇓ Inhibition of astrocyte secreted chon-droitin sulfate proteoglycans Subcutaneous injection Motoneuron survival 61.2% at 12 weeks post-avulsion ⇑ Amount and size of regenerated axons Act as synapse organizing agent Rat None
Resveratrol Drug Topoisomerase II inhibitor Added to nerve graft culture Motoneuron survival 69% at 8 weeks post-avulsion ⇑ Axonal regeneration, Schwann cell migration and myelination Only tried on autologous nerve graft cultures Rat Cancer, Chronic diseases, Aging
Riluzole Drug Inhibitor presynaptic glutamate release Orally Motoneuron survival 70% by 5 weeks post-avulsion ⇑ Myelinated axons in re-implanted nerve root. ⇓ Sensory hypersensitivity and allodynia Administration before 2 week after injury. Maximum effect combined with GDNF Rat Amyotrophic lateral sclerosis, Nervous Depression, Spinal Cord Injury
Lithium Drug ⇑ Endogenous BDNF secretion Orally Motoneuron survival 69% by 12 weeks post-avulsion ⇑ Myelinated axons inside re-implanted nerve root Helps prevent muscle atrophy Rat Bipolar disorder
Minocycline Tetracyclyne derivative Inhibits glial proliferation. Strong anti-inflammatory effect Orally Motoneuron survival 48±7% at 5 weeks. Autonomic neurons ∅ effect Improves axonal sprouting and migration Neurotoxic at high doses.
Prevents and reverses hypersensitivity
Rat, mice Bacterial infections, Stroke
Recombinant erythropoietin Drug Counteracts glutamate’s cytotoxic effect Subcutaneously Motoneuron survival 51.7 ± 0.8% at 12 days post-avulsion Suppresses microglia proliferation. Protects axon regeneration Induces a pro-thrombotic state.
Neuroprotective effect NOT long-lasting
Rat Anemia
FK506-tacrolimus Drug Immunosuppression. Target heat shock protein 90 Sublingual Motoneuron survival not reported. Used ONLY in dorsal nerve root repair ⇑ Regenerating axons penetrating and reaching the posterior horn Immunosuppression. Long-term administration needed Rat Organ transplant immunosuppression
Geldamycin Ansamycin antibiotic On heat shock protein 90. NOT immunosuppression Parenteral injection ⇑ Survival dorsal ganglion neuron. Motoneuron not studied Accelerates axonal regeneration No immunosuppression. Toxic at high doses Rat Cancer
Acamprosate Drug ⇓ Synaptic glutamate Orally Associated with ribavirin ⇑ motoneuron survival by 64.62% at 1 week Associated with ribavirin accelerates axonal regeneration >4 weeks Side effects if ethanol consumption Rat Alcoholism
Ribavirin Drug Synthetic guanosine antiviral properties Orally Associated with acamprosate ⇑ motoneuron survival by 64.62% at 1 week Associated with Acamprosate accelerates axonal regeneration >4 weeks Can induce anemia Rat Hepatitis virus C
N-acetyl cysteine Drug Stabilizes oxidative metabolism Orally Neuron survival 26% motor, 95% sensory Facilitates axonal regeneration Vitamin C counteracts side effects Rat Mucolytic
Glatiramer Drug Immunomodulator Subcutaneously ⇑ Motoneuron survival but NOT quantified Reduction in astrocyte proliferation ⇑ Risk of infection and malignancy Rat Multiple sclerosis

Table 1.

NFs (neurotrophic factors) and drugs used in nerve root reimplantation with their effects.

NF administration improves MN survival as well as synaptic and axonal regrowth [87, 112, 113, 114, 115] improving the NR reimplantation results. NFs enhance Schwann cell migration, axonal regeneration and myelination [8, 16, 69, 93, 105, 116, 117, 118, 119, 120] and delay MN apoptosis—by 6 weeks 80–90% of them are still alive [8, 69, 116, 118, 119, 120, 121]. To be maximally effective, they must be administered locally at the SC-NR interface within the first 3 days and no later than 2 weeks post-avulsion [20, 87, 93, 116]. NFs ought to be applied with Gelfoam or fibrin glue to avoid dilution in the CSF [72], but free intrathecal application by means of an injecting pump is not recommended [122]. Their short half-life limits their use, particularly because NFs have to be applied directly to a surgically exposed SC [123]. Although NFs increase MN survival and axonal regeneration, their effect on muscle recovery and final functional results is very limited [4, 7, 18, 20, 27, 37, 93, 105]. It has been observed that in areas where the concentration of NFs is high, the regenerating axons get trapped and do not grow to reach their final distal targets [18, 102]. Some have cautioned against the possible adverse effects of using NFs in human clinical practice [124]. The currently used NFs are brain-derived neurotrophic factor (BDNF) [115], glial-derived neurotrophic factor (GDNF) [8, 18, 20, 37, 102, 105, 125], ciliary neurotrophic factor (CNTF) [87] and intracellular sigma peptide (ISP) [126]. GDNF shows the strongest action and a single direct application to the SC are enough, provided that they are applied within the first 2 weeks after NRA [18, 20, 37, 102, 116, 127]. GDNF delays MN cell death for 6 weeks, therefore broadening the window for avulsed NR reimplantation [20]. Similarly, the intracellular sigma peptide (ISP) blocks astrocytic inhibitory action, thus facilitating axonal regeneration [126].

Moreover, the distance to cover by the regenerating axons from the SC avulsion site to the muscular end plates is so long that by the time the axons reach their destination, the muscles are atrophic and fibrotic [20, 128]. To avoid and delay this muscle atrophy as much as possible, several strategies have been attempted: manipulating the molecular pathways involved in muscle atrophy [129, 130, 131], nerve transfers from neighboring functioning nerves [132, 133, 134, 135, 136], direct electrical stimulation of the affected muscles [137, 138, 139] and neuronal transplantation inside the denervated muscle [20, 140, 141, 142]. In rats, the combination of GDNF at the SC-NR injury site and embryonic spinal foetal neuron transplant inside the target muscles provided the best possible functional result [20]. These embryonic neurons reinnervate the muscle end plates just after the injury, preventing muscle atrophy while the regenerating axons arrived [20]. However, when the regenerating axons reached the muscular end plates, they had to compete with the already existing axons coming from the locally injected embryonic foetal neurons [20, 140, 143, 144].

Some drugs have been administered to minimize MN apoptosis and improve NR regeneration: resveratrol (3,4′,5-trihydroxystilbene) [145], riluzole (2-amino-6-trifluoromethoxybenzothiazole) [8, 69, 121], lithium [146, 147], minocycline [119], recombinant erythropoietin [118], FK506-tacrolimus [148, 149, 150, 151], geldanamycin [152, 153], acamprosate [67, 154], ribavirin [154], N-acetyl cysteine [155] and glatiramer [156]. Some researchers have administered combinations such as acamprosate and ribavirin [154] or riluzole and GDNF [8]. The main advantage of acamprosate, ribavirin, and riluzole is that they can be administered orally [67, 154, 157].

Resveratrol has been added to the autologous NG culture for a week in the rat experimental C6 NRA and reimplantation model [145], finding that it improves axonal regeneration, Schwann cell migration and myelination and MN survival—69% surviving 8 weeks after NR repair.

In experimental brachial plexus avulsion (BPA) rat models, riluzole has been proved to improve MN survival, prolonging the time period at which reimplantation can be successful [65, 69, 101, 121]. If administered within 2 weeks post-avulsion, riluzole helps to keep 70% of the MNs [65, 69, 121] alive and minimizes the sensory hypersensitivity and allodynia [119]. Its maximum effect is achieved when combined with GDNF [8], and it can be administered orally [157].

In rat, experimental avulsion models and at doses used in the treatment of mood disorders, lithium improves neuronal survival, axonal regeneration and myelination, allowing an earlier and better functional recovery [146, 147]. One of its mechanisms of action is by increasing endogenous BDNF secretion [158]. Its effect on growing axon myelination starts 4 weeks post-NR reimplantation, reaching its pinnacle at 6 weeks and slowing down by 12 weeks [146].

Minocycline is a tetracycline derivative that inhibits glial proliferation [159]—a barrier against axonal and dendrite growth [160]—and decreases neuronal [161] and oligodendrocyte cell loss [120, 162, 163]. Minocycline can cross the blood–brain barrier and has anti-inflammatory properties [120]. In rats, it has been administered intraperitoneally and intrathecally, with better results through the latter route [106]. At low doses, minocycline has neuroprotective properties, but at high concentrations it is neurotoxic [164], among other reasons, because glial proliferation and Wallerian degeneration are a sine qua non for nerve regeneration [106].

Recombinant erythropoietin injected subcutaneously once a day for 3 days has shown neuroprotective properties in a rat NRA experimental model [118]. These neuroprotective properties are short lasting but can help to delay motor neuron apoptosis after NRA, increasing the period in which a NR reimplantation can be undertaken [118]. Recombinant erythropoietin seems to counteract the cytotoxic effect of glutamate, block free radicals, increase the release of neurotransmitters and decrease microglial activation [165]. The positive effects of recombinant erythropoietin are maximal when its administration is started within 96 hours (4 days) after NRA and reimplantation [118]. The side effects related with the administration of this drug—increase in erythrocyte production and a prothrombotic state—are not problematic because this drug is only administered for 3 days [118]. Perhaps administering this drug for a longer period of time could provide additional neuroprotective effects, but 3 days are enough to prolong the period in which a successful NR reimplantation can be performed [118].

FK506-tacrolimus improved the amount of regenerating posterior NR axons penetrating the SC and reaching the posterior horn [151].

Acamprosate is a taurine analogue used to prevent relapse in alcoholic patients that acts as neuroprotective and accelerates axonal regeneration [154, 166].

Ribavirin is a nucleoside antimetabolite antiviral agent that blocks nucleic acid synthesis that is administered together with acamprosate to encourage axonal regeneration [154].

N-Acetyl cysteine administered intraperitoneally and intrathecally in rats enhances the rate of MN survival and facilitates regeneration in case of NR reimplantation [155].

Glatiramer is a polymer of L-alanine, L-glutamic acid, L-lysine and L-tyrosine that structurally resembles the myelin basic protein and that when administered daily reduces the gliosis and the avulsed MN synaptic stripping [156].

To summarize, in NRA reimplantation GDGF applied directly to the anterior SC—to the point where the motor rootlets go out—associated with oral riluzole provides the highest rate of MN survival and axonal regeneration [8]. For the dorsal root, CNTF [87] applied directly to the section of the posterior SC where the sensory rootlets get in combined with oral N-acetyl cysteine [155] allows maximal sensory neuron survival. Other agents could be added, such as oral minocycline [106, 120], tacrolimus [151] or recombinant erythropoietin [118, 165]to reduce the reactive glial proliferation that impairs the axonal regeneration. ISP should be administered subcutaneously to minimize astrocyte inhibition of axonal regeneration [126, 167]. The data are summarized in Table 1.

Another strategy has been to apply pluripotent cells at the SC avulsion site to improve MN survival and axonal regeneration. These have been particularly useful in minimizing neuronal apoptosis. Among them are induced pluripotent stem cells (iPSC) [143], mesenchymal stem cells (MSCs) [168, 169, 170], olfactory ensheathing glial cells (OECs) [85, 171], bone marrow stem cells (BMC) [172], human fibroblast growth factor 2 (FGG2) [95], neuroectodermal stem cells (ESC) [143], murine neural crest stem cells (MNCSC) [173], embryonic stem cell-derived neuron precursors (ESCDNP) [173] and neural progenitor cells (NPC) [140, 141, 168, 174]. The human embryonic stem cells overexpressing human fibroblast growth factor 2 (FGG2) applied at the injury site improved MN survival and reduced the glial reactivity, thus improving the regenerating capacities [95]. However, it has unknown effectivity, only shown in animal experimental studies, and its application in the human being creates ethical issues.

Some researchers have found in vivo that a week time gap between NG harvest and its subsequent use in nerve repair improves the regenerating capacities [175] by increasing the number of Schwann cells and macrophages inside the NG [145, 176, 177] as well as by inducing the local GDNF release [145, 178, 179]. This is another possibility but difficult to use in clinical practice.

A word of caution is to be said about the materials used to glue the peripheral NGs to the SC. Only Tisseel® causes no long-term histological reaction [180, 181], while other preparations available in the market (BioGlue®, Adherus®) induce local fibrous reaction with SC adherences and at times neurological sequelae [181]. BioGlue® when applied close or in contact with nervous tissues can create serious damages [182]. In rats, some researchers have used snake (Crotalus durissus terrificus) venom-derived fibrin glue and reported excellent results [183, 184]. In clinical practice, fibrin glue from human origin is usually used [15, 30, 33, 45, 185].

On the other hand, conduits can be used to substitute autologous NGs. They have been extensively tried in peripheral nerve repairs [186, 187], but in NR reimplantation the data available are more limited [188, 189]. In peripheral nerve repair, these conduits have proved useful up to distances of 70 mm in length [37, 38, 190]. Certainly, the central-peripheral nervous tissue interface is a place in which autologous NFs provided by the autologous NGs play a pivotal role in regeneration of the reimplanted NR [69, 77, 89, 91, 92, 93]. Some researchers have tried nerve conduits enriched with BDNF that have had a good result in a rabbit experimental model [191]. In human clinical practice, there are currently no published reports [45, 74].

However, the applicability of all these studies is limited since they were generated with experimental animal models and with reimplantation immediately following the avulsion. On top of that, the regenerating capacities of the human nervous system are much less than that observed in research animals (the rat especially [73]), and the reimplantation of an avulsed NR has to be delayed weeks or even months until the patient is stabilized from other traumatic lesions and when an adequate diagnosis and treatment strategy are well defined [111].


4. Surgical technique of human NR reimplantation

Surgical techniques can be useful, particularly in complete BPA and with a delay between the injury and the surgical repair of no longer than 4 weeks [45]. Some significant problems are that MN apoptosis is greater as the time goes by [20, 27, 91, 93, 101, 102, 103] and that by 4 weeks, there is a dense scar around the BP as well as the avulsed NRs and in their intervertebral foramina that hinders any surgical manoeuvres [45, 74].

The surgical approaches described can be summarized into posterior subscapular [192], lateral [193], anterolateral [194, 195] and single-stage combined anterior (first) and posterior (second) [33].

4.1. Posterior subscapular approach

With the patient in the prone position, a longitudinal incision is made halfway between the spine and the scapula [39, 192, 196]. The trapezius muscle is sectioned transversally in the direction of its fibers. The rhomboid major and minor muscles are also divided following the direction of their fibers. The T1 transverse process is identified and removed with the aid of a drill. A section of the first rib is also removed. A laminectomy and facetectomy are needed to access the spinal canal. The dura is opened and the dentate ligaments sectioned to rotate the SC to reach the implantation site of the ventral roots. As no access to the anterior structures is possible, another anterior approach to the BP is needed to identify and mobilize it and to pass the NGs from one surgical field to the other [7]. Depending on the degree of bone removal, a posterior cervical fusion might be required. This approach only allows access to the avulsed NRs that lie inside the spinal canal or outside it but very close to the foramina [39]. Only one case was reported in 1995 [39], which did not spark much interest within the BP surgical community. Currently this technique is not used for NR reimplantation.

4.2. Lateral approach

This has been well described in the publications of Carlstedt and co-authors [7, 44, 45, 193]. The patient is placed on the lateral decubitus position with the affected arm at the highest position and slightly rotated outwards with the hand in supination. The head is supported in a Mayfield head clamp (Integra LifeSciences, Austin, Texas, USA) and, slightly laterally, bent towards the healthy side. The idea is not only to allow surgical access to the whole BP but also to the possible donor sensory nerves (median antebrachial cutaneous and radial sensory nerves). The ipsilateral lower limb saphenous nerve can also be accessed with ease. The surgical table is placed in a 15% head-up position to reduce venous bleeding. A skin incision is performed from the mastoid to the clavicle following the posterior border of the sternocleidomastoid muscle [7, 44, 45],or by incising from the sternocleidomastoid muscle-clavicular incision and running parallel to the clavicle about 2 cm above it in the direction of the C7 spinous process [193]. After dissecting the platysma and sternocleidomastoid muscles, the spinal accessory and cervical plexus nerves are identified and referenced with loops. Care has to be taken not to damage the spinal accessory nerve at the junction between the upper and middle-third sternocleidomastoid muscle posterior border. After careful subcutaneous fat dissection, the transverse processes of the cervical vertebrae can be felt deep to the sternocleidomastoid muscle with the tip of the finger. The scalene muscles anterior, middle and posterior as well as the levator scapula muscle are identified. Next, the transverse cervical artery and vein are isolated and referenced. It is best not to sacrifice them as they can be used in the future to vascularise a possible gracilis muscle graft [197]. The BP is fully exposed and the avulsed NRs identified. The avulsed NRs are trimmed until normal-appearing nervous tissue is seen. Many surgeons remove the dorsal root including its ganglion [15, 45]. Unless the NR reimplantation is attempted in the first 2 weeks post-avulsion injury, the BP retracts distally and undergoes fibrotic changes adhering to the nearby structures [1, 26, 33, 198, 199], so the BP has to be completely freed to be able to move it upwards. This maneuver can be troublesome at times due to dense fibrotic tissue, particularly when surgical reimplantation has been delayed over 4 weeks [15, 45]. When this is not possible or the BP cannot regain its former position in contralateral C7 NR transfer, some have shortened the humerus shaft by 4 cm [198]. The alternative is to use long autologous NGs that cover the gap between the SC and the NR remnants [15, 26, 45, 109].

The C5-T1 NR foramina and zygapophyseal joints are approached between the elevator scapula and the middle and posterior scalene muscles. Then the longissimus muscle is split longitudinally to expose the spine. The multifidus muscles are detached from the zygapophyseal joints and laminae. The transverse processes and the anterior and posterior tubercles are exposed by removing all the muscles attaching to them. These bone structures plus a section of the lateral mass are removed and a C5-C7 hemilaminectomy performed. The removed bone pieces are saved for later use.

Care must be taken with the vertebral artery, as it does not need to be mobilized. As most of the lateral mass, the disc and the contralateral facet joints are spared; the procedure usually does not induce spine instability. The avulsed NRs can be identified by pseudomeningoceles. The C5–C7 foramina are exposed with ease, while the C8 and T1 are much more difficult, and some surgeons refuse to do it to concentrate in repairing only the C5–C7 NRs, even if the lower ones are also damaged [45]. This is important because no improvement can be expected in roots that have never been reimplanted and explains one of the reasons why the distal muscles of the hand are seldom reinnervated [15, 45]. Some researchers have proven in rat experimental studies that a single reimplanted NR can attract regenerating axonal sprouts from nearby levels [200].

The dura mater is exposed and opened longitudinally and the dentate ligaments sectioned. Intraoperative neurophysiological monitoring is recommended particularly on rotating the SC and when performing the longitudinal myelotomy and inserting the NGs inside it [45].

4.2.1. Ventral root repair

The SC is rotated, pulling from the dentate ligaments to expose its anterior aspect. Serial 2–3 mm-long stab incisions are done at the same place where the anterior NRs formerly stood. Peripheral nerve sensory NGs (medial antebrachial cutaneous nerve, superficial radial nerve, saphenous nerve) are introduced 1 mm inside the SC tissue [201] and secured with Tisseel fibrin glue (Immuno AG, Vienna, Austria). The distal stumps of these NGs are sutured with the corresponding avulsed NR remnant. The dura mater is repaired with a dural substitute and the suture reinforced with fibrin glue to prevent CSF leaks.

Some anatomical studies have found that the best spot where to insert the NGs in the SC is where the anterior NRs formerly stood and not in the lateral SC side [201]. This latter place is technically easier and achieves some regeneration by lateral MN axon sprouting, but the results are inadequate [201]. As the NG implantation inside the SC will cause a further damage to it [26], suturing the NGs to the SC pial surface in an experimental avulsion model has been tried, finding that it allows adequate MN survival and axonal regeneration [27]. This ventral root pial reimplantation is not only less risky but technically easier [26, 33].

4.2.2. Dorsal rootlet repair

This was first reported in 1997 in an experimental rat NRA model [202]. Peripheral NGs were used to cover the gap between the remaining dorsal NR and the SC. A DREZ longitudinal myelotomy was performed to insert the NGs 2 mm inside the posterior horn. Some regeneration was seen with peroxidase staining [202]. The addition of olfactory ensheathing cells at the DREZ in 2003 did not improve the results [171]. In 2004, Tang et al. [188] also in rats used bioresorbable nerve conduits to repair a 6 mm dorsal NR gap, showing signs of recovery. This repair was enhanced by injecting a viral vector inside the DRG [203]. In 2017, Konig et al. [173] reported the application of murine neural crest stem cells and embryonic stem cell-derived neuron precursors at the DREZ in an experimental rat cervical dorsal NRA showing differentiation into neurons and their migration, transforming into interneurons and facilitating the creation of synapsis with the regenerating axons coming from the reimplanted dorsal NR.

In humans, dorsal rootlet repair has been recently attempted by Carlstedt et al. [97]. As they noticed the extreme difficulty for the growing axons coming from the DRG to cross the glial scar at the surface of the posterior horn, they sectioned the avulsed NR distal to the DRG and sutured the peripheral sensory stump to the posterior horn by means of NGs introduced in the SC through a longitudinal myelotomy. The rationale was to get some sensory recovery from the growing axons of the posterior horn neurons that are expected to grow distally inside the implanted NG [99]. As the neuronal bodies of the DRG are removed, the regeneration has to depend on the neuronal plasticity of neurons coming from the posterior horn that have to stretch their axons to reach the skin though the NGs and peripheral nerves. The results are poor [99, 100], but it is the first strategy that has provided some success in humans. This is not ideal as sensation could be recovered if the dorsal rootlets were replaced by NGs and the tip of those grafts inserted inside the posterior SC horn through a longitudinal myelotomy while maintaining the neuronal bodies that lie at the DRG. This technique proved effective in rats [202], but no attempts in humans have been found in the literature. To improve the results, CNTF [87] should apply locally to the posterior SC at the DREZ associated with N-acetyl cysteine [155] orally to allow maximal sensory neuron survival. Oral minocycline [106, 120], oral tacrolimus [151] or subcutaneous recombinant erythropoietin [118, 165] could be also administered to reduce the reactive glial proliferation that acts as a barrier against dorsal root axonal regeneration.

4.2.3. Wound closure

The dura mater is closed with a dural substitute and reinforced with fibrin glue to prevent CSF leaks. The morcellized bone obtained from the transverse processes and lateral masses supplemented together with demineralized bone matrix is laid on the cervical spinal column defect to enhance bone fusion. A lumbar drain is inserted and kept for 5 days to prevent CSF leaks.

Postoperatively, patients are kept with a sling for 6 weeks before starting any passive movements, to prevent NG dislodgement [45]. Cervical X-rays are taken every 3 months for a year to detect any possible instability that might require a cervical fusion.

The most important disadvantage of this approach is that it entails extensive muscular damage, particularly at the scalene muscles [33]. The most significant advantage is that the NGs needed for the repair are the shortest of all the NRA reimplantation approaches [45, 193].

4.3. Anterolateral approach

It is first described by George et al. for the treatment of cervical spinal spondylosis and tumors [204, 205]. This approach is much more direct but demands a partial multilevel oblique partial corpectomy of the affected levels that can be C4 to T1 when the whole BP is involved. This involves an extensive anterior cervical fusion, not optimal for younger individuals due to its possible long-term consequences [206]. The anterolateral approach provides good access to the BP and ventral NR, but the dorsal NR cannot be reimplanted [195]. This approach has been reported in research animals—cats [207, 208]—in ten cadavers and four clinical cases [194], but no long-term clinical results have been reported.

4.4. Single-stage combined anterior (first) and posterior (second) approach

The antecedent of this approach is the two-stage combined approach posterior (first) and anterior (some days later) [185]. In the first stage, the cervical spinal canal was approached with the patient prone. A C4–T1 laminectomy with medial-third facetectomy was performed and the SC inspected after longitudinal dural opening. The dentate ligaments were sectioned and SC rotated and inspected looking for avulsed NR. In case the avulsed NRts were inside the dura mater, they were reimplanted where they formerly stood. Both ventral and dorsal NRs were reimplanted. When the NRs were outside the spinal canal, NGs were inserted and sutured to the SC tissue through small myelotomies and their distal end tunneled through the paraspinal muscles and placed in the supraclavicular area with two metallic hemoclips to facilitate their identification in the future. The dura mater was sutured and sealed with fibrin glue. A posterior mass cervical fusion was performed to prevent postoperative kyphotic deformities. Some days later the patient was taken back to the operating room and in the supine position the BP identified and isolated in the supraclavicular region. The NG distal ends were localized through the hemoclips with X-ray guidance and sutured to the corresponding BP cords. Apart from the original report [116], no further publications on this seem to exist.

The single-stage combined anterior (first) and posterior (second) approach was reported by Amr el al. in 2009 [33]. The patient is placed in the lateral decubitus position and the skin sterilized front and back of neck and chest as well as the whole affected upper limb and both lower limbs. Then the patient is rotated backwards and placed supine. In this position a traditional BP exploration is done through a transverse supraclavicular incision. If needed, a second incision perpendicular to it can be done following the delto-pectoral groove. This allows exploration of the infra-clavicular BP, particularly when it has migrated distally. Once the whole BP is dissected free and the damages evaluated, several peripheral sensory NGs are obtained from the affected upper limb and both lower limbs. These grafts are sutured to the cords of the avulsed NR.

Next, the patient is placed again in the lateral position. Through a posterior midline incision from occiput to T2, the whole cervical spine is exposed. The spinal muscles are detached from the spinous process and separated laterally. A laminectomy and partial medial facetectomy C4–T1 are performed on the affected side. The dura is opened through a longitudinal incision and the dentate ligaments sectioned. The NG that had been previously sutured to the BP cords in an end-to-side versus end-to-end technique [33, 209] is passed subcutaneously from the anterior surgical field to the laminectomy area. These NG needs to be long enough to cover the distance between the SC and the BP. Then the proximal ends of the NGs are sutured subpially in a longitudinal fashion, parallel to the side where the ventral roots stood. No SC incisions are performed. The proximal ends of the NGs are sutured intradurally to C4 above and to T1 below. In the only publication that we have found, the dorsal NRs are not repaired [33]. The dura is closed with interrupted stitches reinforced with fibrin glue. No cervical fusion is applied.

The advantage of this double approach is that it is more conservative to the muscles. The disadvantage is that long NGs are needed, making the distance between the motoneuron and the muscular end plates still larger. To the best of our knowledge, there is only a single publication attesting the validity of this technique [33]. It is of particular interest that ventral NR regeneration can be achieved by laying the NGs subpially at the SC without having to insert them inside the SC tissue through myelotomies [33].


5. Clinical results in human beings

Some clinical studies have reported definitive although limited motor and sensory improvements particularly in the proximal limb areas after NR reimplantation in complete BPAs [15, 30, 32, 33, 45, 185]. The best motor recovery was seen at the deltoid, pectoralis, infraspinatus, biceps and triceps muscles [15, 30, 45, 185, 209]. One patient showed signs of partial recovery of the flexor digitorum superficialis and another of the first dorsal interosseous muscle [45]. A functional recovery of the hand has only been reported in a 9-year-old child with a complete BPA [29]. Hand intrinsic muscle motor grade 2 recovery was reported by Amr et al. [33]. The best sensory improvement was patent at dermatomes C5, C6 and T1, particularly at C5 [33, 45]. One of the reasons by which only proximal muscles show signs of reinnervation in the work of Kachramanoglou et al. is because only the C5–C7 NRs are reimplanted as C8 and T1 are more technically demanding and they were reluctant to risk neurological complications on handling the SC at these levels [45]. This could also be the reason by which Amr et al. [33] report hand intrinsic muscle grade 2 motor recovery, as they did repair the C8 and T1 roots. Another extremely important reason is that when the regenerating axons reach the distal limb muscles, they are already atrophied and fibrotic [72, 73]. The C5 and T1 sensory recovery can in part be due to overlapping sensory covering from nearby dermatomes (C4 for C5 and T2 for T1) [32, 45].


6. Conclusions

NRA keeps being in an area in which improvement is desperately needed, particularly in complete BPAs in which not many alternatives are possible. As clinical results in humans keep being dismal, further research is needed. The administration of drugs, preferably orally, has to be pursued to find a combination of them that helps to achieve a successful limb recovery. NR reimplantation has to be undertaken as soon as the patients’ clinical condition allows it. Ventral NRt implantation provides better results than its posterior counterparts.



BDNFbrain-derived neurotrophic factor
BMCbone marrow stem cells
BPbrachial plexus
BPAbrachial plexus avulsion
CNFciliary neurotrophic factor
GDNFglial-derived neurotrophic factor
iPSCinduced pluripotent stem cells
ISPintracellular sigma peptide
MNmotor neuron
MSCsmesenchymal stem cells
NFneurotrophic factor
NGsnerve grafts
NPCneural progenitor cells
NRnerve root
NRAnerve root avulsion
NRtsnerve rootlets
NSCneuroectodermal stem cells
OECsolfactory ensheathing glial cells
SCspinal cord


  1. 1. Abou-Al-Shaar H, Karsy M, Ravindra V, Joyce E, Mahan MA. Acute repair of traumatic pan-brachial plexus injury: Technical considerations and approaches. Neurosurgical Focus. 2018;44(VideoSuppl1):V4. DOI: 10.3171/2018.1.FocusVid.17569
  2. 2. Barman A, Chatterjee A, Prakash H, Viswanathan A, Tharion G, Thomas R. Traumatic brachial plexus injury: Electrodiagnostic findings from 111 patients in a tertiary care hospital in India. Injury. 2012;43(11):1943-1948. DOI: 10.1016/j.injury.2012.07.182
  3. 3. Bertelli JA, Ghizoni MF, Soldado F. Patterns of brachial plexus stretch palsy in a prospective series of 565 surgically treated patients. Journal of Hand Surgery. 2017;42(6):443-446.e2. DOI: 10.1016/j.jhsa.2017.03.021
  4. 4. Hoffmann CF, Thomeer RT, Marani E. Reimplantation of ventral rootlets into the cervical spinal cord after their avulsion: An anterior surgical approach. Clinical Neurology and Neurosurgery. 1993;95(Suppl):S112-S118
  5. 5. Okby R, Sheiner E. Risk factors for neonatal brachial plexus paralysis. Archives of Gynecology and Obstetrics. 2012;286(2):333-336. DOI: 10.1007/s00404-012-2272-z
  6. 6. Chambers JA, Hiles CL, Keene BP. Brachial plexus injury management in military casualties: Who, what, when, why, and how. Military Medicine. 2014;179(6):640-644. DOI: 10.7205/MILMED-D-13-00457
  7. 7. Carlstedt T, Anand P, Hallin R, Misra PV, Norén G, Seferlis T. Spinal nerve root repair and reimplantation of avulsed ventral roots into the spinal cord after brachial plexus injury. Journal of Neurosurgery. 2000;93(2 Suppl):237-247
  8. 8. Bergerot A, Shortland PJ, Anand P, Hunt SP, Carlstedt T. Co-treatment with riluzole and GDNF is necessary for functional recovery after ventral root avulsion injury. Experimental Neurology. 2004;187(2):359-366. DOI: 10.1016/j.expneurol.2004.02.003
  9. 9. Ruven C, Chan T-K, Wu W. Spinal root avulsion: An excellent model for studying motoneuron degeneration and regeneration after severe axonal injury. Neural Regeneration Research. 2014;9(2):117-118. DOI: 10.4103/1673-5374.125338
  10. 10. Martin LJ, Kaiser A, Price AC. Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves with oxidative stress and is apoptosis. Journal of Neurobiology. 1999;40(2):185-201
  11. 11. Martin LJ, Liu Z. Injury-induced spinal motor neuron apoptosis is preceded by DNA single-strand breaks and is p53- and Bax-dependent. Journal of Neurobiology. 2002;50(3):181-197
  12. 12. Hoang TX, Nieto JH, Tillakaratne NJK, Havton LA. Autonomic and motor neuron death is progressive and parallel in a lumbosacral ventral root avulsion model of cauda equina injury. The Journal of Comparative Neurology. 2003;467(4):477-486. DOI: 10.1002/cne.10928
  13. 13. Koliatsos VE, Price WL, Pardo CA, Price DL. Ventral root avulsion: An experimental model of death of adult motor neurons. The Journal of Comparative Neurology. 1994;342(1):35-44. DOI: 10.1002/cne.903420105
  14. 14. Havton LA, Carlstedt T. Repair and rehabilitation of plexus and root avulsions in animal models and patients. Current Opinion in Neurology. 2009;22(6):570-574. DOI: 10.1097/WCO.0b013e328331b63f
  15. 15. Carlstedt T. Root repair review: Basic science background and clinical outcome. Restorative Neurology and Neuroscience. 2008;26(2-3):225-241
  16. 16. Nógrádi A, Vrbová G. Improved motor function of denervated rat hindlimb muscles induced by embryonic spinal cord grafts. The European Journal of Neuroscience. 1996;8(10):2198-2203
  17. 17. Chew DJ, Leinster VHL, Sakthithasan M, Robson LG, Carlstedt T, Shortland PJ. Cell death after dorsal root injury. Neuroscience Letters. 2008;433(3):231-234. DOI: 10.1016/j.neulet.2008.01.012
  18. 18. Blits B, Carlstedt TP, Ruitenberg MJ, et al. Rescue and sprouting of motoneurons following ventral root avulsion and reimplantation combined with intraspinal adeno-associated viral vector-mediated expression of glial cell line-derived neurotrophic factor or brain-derived neurotrophic factor. Experimental Neurology. 2004;189(2):303-316. DOI: 10.1016/j.expneurol.2004.05.014
  19. 19. Bertelli JA, Ghizoni MF. Reconstruction of C5 and C6 brachial plexus avulsion injury by multiple nerve transfers: Spinal accessory to suprascapular, ulnar fascicles to biceps branch, and triceps long or lateral head branch to axillary nerve. Journal of Hand Surgery. 2004;29(1):131-139
  20. 20. Ruven C, Badea S-R, Wong W-M, Wu W. Combination treatment with exogenous GDNF and fetal spinal cord cells results in better Motoneuron survival and functional recovery after avulsion injury with delayed root reimplantation. Journal of Neuropathology and Experimental Neurology. 2018;77(4):325-343. DOI: 10.1093/jnen/nly009
  21. 21. Jeanmonod D, Sindou M, Mauguière F. Intraoperative electrophysiological recordings during microsurgical DREZ-tomies in man. Stereotactic and Functional Neurosurgery. 1990;54-55:80-85. DOI: 10.1159/000100195
  22. 22. Guenot M, Hupe JM, Mertens P, Ainsworth A, Bullier J, Sindou M. A new type of microelectrode for obtaining unitary recordings in the human spinal cord. Journal of Neurosurgery. 1999;91(1 Suppl):25-32
  23. 23. Carlstedt T, Havton L. The longitudinal spinal cord injury: lessons from intraspinal plexus, cauda equina and medullary conus lesions. Handbook of Clinical Neurology. 2012;109:337-354. DOI: 10.1016/B978-0-444-52137-8.00021-8
  24. 24. Htut M, Misra P, Anand P, Birch R, Carlstedt T. Pain phenomena and sensory recovery following brachial plexus avulsion injury and surgical repairs. Journal of Hand Surgery (Edinburgh, Scotland). 2006;31(6):596-605. DOI: 10.1016/j.jhsb.2006.04.027
  25. 25. Vredeveld JW, Blaauw G, Slooff BA, Richards R, Rozeman SC. The findings in paediatric obstetric brachial palsy differ from those in older patients: A suggested explanation. Developmental Medicine and Child Neurology. 2000;42(3):158-161
  26. 26. Su H, Yuan Q, Qin D, et al. Ventral root re-implantation is better than peripheral nerve transplantation for motoneuron survival and regeneration after spinal root avulsion injury. BMC Surgery. 2013;13:21. DOI: 10.1186/1471-2482-13-21
  27. 27. Gu H-Y, Chai H, Zhang J-Y, et al. Survival, regeneration and functional recovery of motoneurons after delayed reimplantation of avulsed spinal root in adult rat. Experimental Neurology. 2005;192(1):89-99. DOI: 10.1016/j.expneurol.2004.10.019
  28. 28. Chuang T-Y, Huang M-C, Chen K-C, et al. Forelimb muscle activity following nerve graft repair of ventral roots in the rat cervical spinal cord. Life Sciences. 2002;71(5):487-496
  29. 29. Carlstedt T, Anand P, Htut M, Misra P, Svensson M. Restoration of hand function and so called “breathing arm” after intraspinal repair of C5-T1 brachial plexus avulsion injury. Case report. Neurosurgical Focus. 2004;16(5):E7
  30. 30. Htut M, Misra VP, Anand P, Birch R, Carlstedt T. Motor recovery and the breathing arm after brachial plexus surgical repairs, including re-implantation of avulsed spinal roots into the spinal cord. The Journal of Hand Surgery, European Volume. 2007;32(2):170-178. DOI: 10.1016/J.JHSB.2006.11.011
  31. 31. Wu W, Chai H, Zhang J, Gu H, Xie Y, Zhou L. Delayed implantation of a peripheral nerve graft reduces motoneuron survival but does not affect regeneration following spinal root avulsion in adult rats. Journal of Neurotrauma. 2004;21(8):1050-1058. DOI: 10.1089/0897715041651006
  32. 32. Bertelli JA, Ghizoni MF. Brachial plexus avulsion injury repairs with nerve transfers and nerve grafts directly implanted into the spinal cord yield partial recovery of shoulder and elbow movements. Neurosurgery. 2003;52(6):1385-1389-1390
  33. 33. Amr SM, Essam AM, Abdel-Meguid AMS, Kholeif AM, Moharram AN, El-Sadek RER. Direct cord implantation in brachial plexus avulsions: Revised technique using a single stage combined anterior (first) posterior (second) approach and end-to-side side-to-side grafting neurorrhaphy. Journal of Brachial Plexus and Peripheral Nerve Injury. 2009;4:8. DOI: 10.1186/1749-7221-4-8
  34. 34. Nichols CM, Brenner MJ, Fox IK, et al. Effects of motor versus sensory nerve grafts on peripheral nerve regeneration. Experimental Neurology. 2004;190(2):347-355. DOI: 10.1016/j.expneurol.2004.08.003
  35. 35. Chu T-H, Du Y, Wu W. Motor nerve graft is better than sensory nerve graft for survival and regeneration of motoneurons after spinal root avulsion in adult rats. Experimental Neurology. 2008;212(2):562-565. DOI: 10.1016/j.expneurol.2008.05.001
  36. 36. Lin Y-L, Chang K-T, Lin C-T, et al. Repairing the ventral root is sufficient for simultaneous motor and sensory recovery in multiple complete cervical root transection injuries. Life Sciences. 2014;109(1):44-49. DOI: 10.1016/j.lfs.2014.06.001
  37. 37. Chu T-H, Wang L, Guo A, Chan VW-K, Wong CW-M, Wu W. GDNF-treated acellular nerve graft promotes motoneuron axon regeneration after implantation into cervical root avulsed spinal cord. Neuropathology and Applied Neurobiology. 2012;38(7):681-695. DOI: 10.1111/j.1365-2990.2012.01253.x
  38. 38. Kassar-Duchossoy L, Duchossoy Y, Rhrich-Haddout F, Horvat JC. Reinnervation of a denervated skeletal muscle by spinal axons regenerating through a collagen channel directly implanted into the rat spinal cord. Brain Research. 2001;908(1):25-34
  39. 39. Carlstedt T, Grane P, Hallin RG, Norén G. Return of function after spinal cord implantation of avulsed spinal nerve roots. Lancet Lond Engl. 1995;346(8986):1323-1325
  40. 40. Carlstedt T, Lindå H, Cullheim S, Risling M. Reinnervation of hind limb muscles after ventral root avulsion and implantation in the lumbar spinal cord of the adult rat. Acta Physiologica Scandinavica. 1986;128(4):645-646. DOI: 10.1111/j.1748-1716.1986.tb08024.x
  41. 41. Cullheim S, Carlstedt T, Lindå H, Risling M, Ulfhake B. Motoneurons reinnervate skeletal muscle after ventral root implantation into the spinal cord of the cat. Neuroscience. 1989;29(3):725-733
  42. 42. Carlstedt TP, Hallin RG, Hedström KG, Nilsson-Remahl IA. Functional recovery in primates with brachial plexus injury after spinal cord implantation of avulsed ventral roots. Journal of Neurology, Neurosurgery, and Psychiatry. 1993;56(6):649-654
  43. 43. Hallin RG, Carlstedt T, Nilsson-Remahl I, Risling M. Spinal cord implantation of avulsed ventral roots in primates; correlation between restored motor function and morphology. Experimental Brain Research. 1999;124(3):304-310
  44. 44. Carlstedt T, Norén G. Repair of ruptured spinal nerve roots in a brachial plexus lesion. Case report. Journal of Neurosurgery. 1995;82(4):661-663. DOI: 10.3171/jns.1995.82.4.0661
  45. 45. Kachramanoglou C, Carlstedt T, Koltzenburg M, Choi D. Long-term outcome of brachial plexus reimplantation after complete brachial plexus avulsion injury. World Neurosurgery. 2017;103:28-36. DOI: 10.1016/j.wneu.2017.03.052
  46. 46. Fraher JP. The transitional zone and CNS regeneration. Journal of Anatomy. 2000;196(Pt 1):137-158
  47. 47. Madduri S, Gander B. Schwann cell delivery of neurotrophic factors for peripheral nerve regeneration. Journal of the Peripheral Nervous System. 2010;15(2):93-103. DOI: 10.1111/j.1529-8027.2010.00257.x
  48. 48. Bigbee AJ, Hoang TX, Havton LA. At-level neuropathic pain is induced by lumbosacral ventral root avulsion injury and ameliorated by root reimplantation into the spinal cord. Experimental Neurology. 2007;204(1):273-282. DOI: 10.1016/j.expneurol.2006.11.003
  49. 49. Teixeira MJ, da Paz MG da S, Bina MT, et al. Neuropathic pain after brachial plexus avulsion—Central and peripheral mechanisms. BMC Neurology. 2015;15:73. DOI: 10.1186/s12883-015-0329-x
  50. 50. Yuan Q, Xie Y, So K-F, Wu W. Inflammatory response associated with axonal injury to spinal motoneurons in newborn rats. Developmental Neuroscience. 2003;25(1):72-78. DOI: 10.1159/000071470
  51. 51. Carlstedt T, Cullheim S, Risling M, Ulfhake B. Nerve fibre regeneration across the PNS-CNS interface at the root-spinal cord junction. Brain Research Bulletin. 1989;22(1):93-102
  52. 52. Carlstedt T. Nerve fibre regeneration across the peripheral-central transitional zone. Journal of Anatomy. 1997;190 (Pt 1:51-56
  53. 53. Risling M, Sörbye K, Cullheim S. Aberrant regeneration of motor axons into the pia mater after ventral root neuroma formation. Brain Research. 1992;570(1-2):27-34
  54. 54. Remahl S, Angeria M, Remahl IN, Carlstedt T, Risling M. Observations at the CNS-PNS border of ventral roots connected to a neuroma. Frontiers in Neurology. 2010;1:136. DOI: 10.3389/fneur.2010.00136
  55. 55. Ohlsson M, Nieto JH, Christe KL, Havton LA. Long-term effects of a lumbosacral ventral root avulsion injury on axotomized motor neurons and avulsed ventral roots in a non-human primate model of cauda equina injury. Neuroscience. 2013;250:129-139. DOI: 10.1016/j.neuroscience.2013.06.054
  56. 56. Ohlsson M, Hoang TX, Wu J, Havton LA. Glial reactions in a rodent cauda equina injury and repair model. Experimental Brain Research. 2006;170(1):52-60. DOI: 10.1007/s00221-005-0188-6
  57. 57. Silver J, Miller JH. Regeneration beyond the glial scar. Nature Reviews. Neuroscience. 2004;5(2):146-156. DOI: 10.1038/nrn1326
  58. 58. Yick LW, Wu W, So KF, Yip HK, Shum DK. Chondroitinase ABC promotes axonal regeneration of Clarke’s neurons after spinal cord injury. Neuroreport. 2000;11(5):1063-1067
  59. 59. McKeon RJ, Schreiber RC, Rudge JS, Silver J. Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes. Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 1991;11(11):3398-3411
  60. 60. Caroni P, Schwab ME. Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading. The Journal of Cell Biology. 1988;106(4):1281-1288
  61. 61. Wang KC, Koprivica V, Kim JA, et al. Oligodendrocyte-myelin glycoprotein is a Nogo receptor ligand that inhibits neurite outgrowth. Nature. 2002;417(6892):941-944. DOI: 10.1038/nature00867
  62. 62. Thanos S, Vanselow J. The effect of central and peripheral neuroglia on the regeneration of the optic nerve. Fortschritte Ophthalmologie. 1989;86(2):172-175
  63. 63. Pasterkamp RJ, Verhaagen J. Emerging roles for semaphorins in neural regeneration. Brain Research. Brain Research Reviews. 2001;35(1):36-54
  64. 64. Giulian D. Reactive glia as rivals in regulating neuronal survival. Glia. 1993;7(1):102-110. DOI: 10.1002/glia.440070116
  65. 65. Nógrádi A, Szabó A, Pintér S, Vrbová G. Delayed riluzole treatment is able to rescue injured rat spinal motoneurons. Neuroscience. 2007;144(2):431-438. DOI: 10.1016/j.neuroscience.2006.09.046
  66. 66. Wu W. Expression of nitric-oxide synthase (NOS) in injured CNS neurons as shown by NADPH diaphorase histochemistry. Experimental Neurology. 1993;120(2):153-159. DOI: 10.1006/exnr.1993.1050
  67. 67. Casas C, Isus L, Herrando-Grabulosa M, et al. Network-based proteomic approaches reveal the neurodegenerative, neuroprotective and pain-related mechanisms involved after retrograde axonal damage. Scientific Reports. 2015;5:9185. DOI: 10.1038/srep09185
  68. 68. Penas C, Casas C, Robert I, Forés J, Navarro X. Cytoskeletal and activity-related changes in spinal motoneurons after root avulsion. Journal of Neurotrauma. 2009;26(5):763-779. DOI: 10.1089/neu.2008.0661
  69. 69. Pintér S, Gloviczki B, Szabó A, Márton G, Nógrádi A. Increased survival and reinnervation of cervical motoneurons by riluzole after avulsion of the C7 ventral root. Journal of Neurotrauma. 2010;27(12):2273-2282. DOI: 10.1089/neu.2010.1445
  70. 70. Gu Y, Spasic Z, Wu W. The effects of remaining axons on motoneuron survival and NOS expression following axotomy in the adult rat. Developmental Neuroscience. 1997;19(3):255-259. DOI: 10.1159/000111214
  71. 71. Wu W, Li L. Inhibition of nitric oxide synthase reduces motoneuron death due to spinal root avulsion. Neuroscience Letters. 1993;153(2):121-124
  72. 72. Eggers R, Tannemaat MR, De Winter F, Malessy MJA, Verhaagen J. Clinical and neurobiological advances in promoting regeneration of the ventral root avulsion lesion. The European Journal of Neuroscience. 2016;43(3):318-335. DOI: 10.1111/ejn.13089
  73. 73. Seddon HJ, Medawar PB, Smith H. Rate of regeneration of peripheral nerves in man. The Journal of Physiology. 1943;102(2):191-215
  74. 74. Carlstedt T. New treatments for spinal nerve root avulsion injury. Frontiers in Neurology. 2016;7:135. DOI: 10.3389/fneur.2016.00135
  75. 75. Lindå H, Risling M, Cullheim S. “Dendraxons” in regenerating motoneurons in the cat: Do dendrites generate new axons after central axotomy? Brain Research. 1985;358(1-2):329-333
  76. 76. Hoang TX, Nieto JH, Havton LA. Regenerating supernumerary axons are cholinergic and emerge from both autonomic and motor neurons in the rat spinal cord. Neuroscience. 2005;136(2):417-423. DOI: 10.1016/j.neuroscience.2005.08.022
  77. 77. Han L, Kan S, Yuan J. Experimental study on reimplantation of ventral root into spinal cord after brachial plexus avulsion. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi Zhongguo Xiufu Chongjian Waike Zazhi—Chinese Journal of Reparative and Reconstructive Surgery. 2007;21(9):948-952
  78. 78. Hoffmann CF, Choufoer H, Marani E, Thomeer RT. Ultrastructural study on avulsion effects of the cat cervical moto-axonal pathways in the spinal cord. Clinical Neurology and Neurosurgery. 1993;95(Suppl):S39-S47
  79. 79. Kozlova EN. Strategies to repair lost sensory connections to the spinal cord. Molekuliarnaia Biologiia (Mosk). 2008;42(5):820-829
  80. 80. Schlegel N, Asan E, Hofmann GO, Lang EM. Reactive changes in dorsal roots and dorsal root ganglia after C7 dorsal rhizotomy and ventral root avulsion/replantation in rabbits. Journal of Anatomy. 2007;210(3):336-351. DOI: 10.1111/j.1469-7580.2007.00695.x
  81. 81. Carlstedt T. Regenerating axons form nerve terminals at astrocytes. Brain Research. 1985;347(1):188-191
  82. 82. Novikov L, Novikova L, Kellerth JO. Brain-derived neurotrophic factor promotes survival and blocks nitric oxide synthase expression in adult rat spinal motoneurons after ventral root avulsion. Neuroscience Letters. 1995;200(1):45-48
  83. 83. Eggers R, Tannemaat MR, Ehlert EM, Verhaagen J. A spatio-temporal analysis of motoneuron survival, axonal regeneration and neurotrophic factor expression after lumbar ventral root avulsion and implantation. Experimental Neurology. 2010;223(1):207-220. DOI: 10.1016/j.expneurol.2009.07.021
  84. 84. Kemp SWP, Chiang CD, Liu EH, et al. Characterization of neuronal death and functional deficits following nerve injury during the early postnatal developmental period in rats. Developmental Neuroscience. 2015;37(1):66-77. DOI: 10.1159/000368769
  85. 85. Ibrahim AG, Kirkwood PA, Raisman G, Li Y. Restoration of hand function in a rat model of repair of brachial plexus injury. Brain: A Journal of Neurology. 2009;132(Pt 5):1268-1276. DOI: 10.1093/brain/awp030
  86. 86. Jivan S, Novikova LN, Wiberg M, Novikov LN. The effects of delayed nerve repair on neuronal survival and axonal regeneration after seventh cervical spinal nerve axotomy in adult rats. Experimental Brain Research. 2006;170(2):245-254. DOI: 10.1007/s00221-005-0207-7
  87. 87. Lang EM, Asan E, Plesnila N, Hofmann GO, Sendtner M. Motoneuron survival after C7 nerve root avulsion and replantation in the adult rabbit: Effects of local ciliary neurotrophic factor and brain-derived neurotrophic factor application. Plastic and Reconstructive Surgery. 2005;115(7):2042-2050
  88. 88. Chuang DC, Lee GW, Hashem F, Wei FC. Restoration of shoulder abduction by nerve transfer in avulsed brachial plexus injury: Evaluation of 99 patients with various nerve transfers. Plastic and Reconstructive Surgery. 1995;96(1):122-128
  89. 89. Hoang TX, Pikov V, Havton LA. Functional reinnervation of the rat lower urinary tract after cauda equina injury and repair. Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2006;26(34):8672-8679. DOI: 10.1523/JNEUROSCI.1259-06.2006
  90. 90. Bilgihan A, Türközkan N, Aricioğlu A, Aykol S, Cevik C, Göksel M. The effect of deferoxamine on brain lipid peroxide levels and Na-K ATPase activity following experimental subarachnoid hemorrhage. General Pharmacology. 1994;25(3):495-497
  91. 91. Carlstedt T. Approaches permitting and enhancing motoneuron regeneration after spinal cord, ventral root, plexus and peripheral nerve injuries. Current Opinion in Neurology. 2000;13(6):683-686
  92. 92. Carlstedt TP. Spinal nerve root injuries in brachial plexus lesions: Basic science and clinical application of new surgical strategies. A review. Microsurgery. 1995;16(1):13-16
  93. 93. Chai H, Wu W, So KF, Yip HK. Survival and regeneration of motoneurons in adult rats by reimplantation of ventral root following spinal root avulsion. Neuroreport. 2000;11(6):1249-1252
  94. 94. Boyd JG, Gordon T. Neurotrophic factors and their receptors in axonal regeneration and functional recovery after peripheral nerve injury. Molecular Neurobiology. 2003;27(3):277-324. DOI: 10.1385/MN:27:3:277
  95. 95. Araújo MR, Kyrylenko S, Spejo AB, et al. Transgenic human embryonic stem cells overexpressing FGF2 stimulate neuroprotection following spinal cord ventral root avulsion. Experimental Neurology. 2017;294:45-57. DOI: 10.1016/j.expneurol.2017.04.009
  96. 96. Carlstedt T, Aldskogius H, Hallin RG, Nilsson-Remahl I. Novel surgical strategies to correct neural deficits following experimental spinal nerve root lesions. Brain Research Bulletin. 1993;30(3-4):447-451
  97. 97. Carlstedt T, James N, Risling M. Surgical reconstruction of spinal cord circuit provides functional return in humans. Neural Regeneration Research. 2017;12(12):1960-1963. DOI: 10.4103/1673-5374.221145
  98. 98. Wang L, Yuzhou L, Yingjie Z, Jie L, Xin Z. A new rat model of neuropathic pain: Complete brachial plexus avulsion. Neuroscience Letters. 2015;589:52-56. DOI: 10.1016/j.neulet.2015.01.033
  99. 99. James ND, Angéria M, Bradbury EJ, et al. Structural and functional substitution of deleted primary sensory neurons by new growth from intrinsic spinal cord nerve cells: An alternative concept in reconstruction of spinal cord circuits. Frontiers in Neurology. 2017;8:358. DOI: 10.3389/fneur.2017.00358
  100. 100. Carlstedt T, Misra VP, Papadaki A, McRobbie D, Anand P. Return of spinal reflex after spinal cord surgery for brachial plexus avulsion injury. Journal of Neurosurgery. 2012;116(2):414-417. DOI: 10.3171/2011.7.JNS111106
  101. 101. Gloviczki B, Török DG, Márton G, et al. Delayed spinal cord-brachial plexus reconnection after C7 ventral root avulsion: The effect of Reinnervating Motoneurons rescued by Riluzole treatment. Journal of Neurotrauma. 2017;34(15):2364-2374. DOI: 10.1089/neu.2016.4754
  102. 102. Eggers R, Hendriks WTJ, Tannemaat MR, et al. Neuroregenerative effects of lentiviral vector-mediated GDNF expression in reimplanted ventral roots. Molecular and Cellular Neurosciences. 2008;39(1):105-117. DOI: 10.1016/j.mcn.2008.05.018
  103. 103. Inciong JG, Marrocco WC, Terzis JK. Efficacy of intervention strategies in a brachial plexus global avulsion model in the rat. Plastic and Reconstructive Surgery. 2000;105(6):2059-2071
  104. 104. Noguchi T, Ohta S, Kakinoki R, Kaizawa Y, Matsuda S. A new cervical nerve root avulsion model using a posterior extra-vertebral approach in rats. Journal of Brachial Plexus and Peripheral Nerve Injury. 2013;8(1):8. DOI: 10.1186/1749-7221-8-8
  105. 105. Wu W, Li L, Yick L-W, et al. GDNF and BDNF alter the expression of neuronal NOS, c-Jun, and p75 and prevent motoneuron death following spinal root avulsion in adult rats. Journal of Neurotrauma. 2003;20(6):603-612. DOI: 10.1089/089771503767168528
  106. 106. Chin TY, Kiat SS, Faizul HG, Wu W, Abdullah JM. The effects of minocycline on spinal root avulsion injury in rat model. Malaysian Journal of Medical Sciences. 2017;24(1):31-39. DOI: 10.21315/mjms2017.24.1.4
  107. 107. He J-W, Hirata K, Wang S, Kawabuchi M. Expression of nitric oxide synthase and 27-kD heat shock protein in motor neurons of ventral root-avulsed rats. Archives of Histology and Cytology. 2003;66(1):83-93
  108. 108. Chang HH, Havton LA. A ventral root avulsion injury model for neurogenic underactive bladder studies. Experimental Neurology. 2016;285(Pt B):190-196. DOI: 10.1016/j.expneurol.2016.05.026
  109. 109. Wu W, Han K, Li L, Schinco FP. Implantation of PNS graft inhibits the induction of neuronal nitric oxide synthase and enhances the survival of spinal motoneurons following root avulsion. Experimental Neurology. 1994;129(2):335-339. DOI: 10.1006/exnr.1994.1176
  110. 110. Hoang TX, Havton LA. A single re-implanted ventral root exerts neurotropic effects over multiple spinal cord segments in the adult rat. Experimental Brain Research. 2006;169(2):208-217. DOI: 10.1007/s00221-005-0137-4
  111. 111. Terzis JK, Vekris MD, Soucacos PN. Brachial plexus root avulsions. World Journal of Surgery. 2001;25(8):1049-1061
  112. 112. Koliatsos VE, Clatterbuck RE, Winslow JW, Cayouette MH, Price DL. Evidence that brain-derived neurotrophic factor is a trophic factor for motor neurons in vivo. Neuron. 1993;10(3):359-367
  113. 113. Henderson CE, Phillips HS, Pollock RA, et al. GDNF: A potent survival factor for motoneurons present in peripheral nerve and muscle. Science. 1994;266(5187):1062-1064
  114. 114. Vejsada R, Sagot Y, Kato AC. Quantitative comparison of the transient rescue effects of neurotrophic factors on axotomized motoneurons in vivo. The European Journal of Neuroscience. 1995;7(1):108-115
  115. 115. Kishino A, Ishige Y, Tatsuno T, Nakayama C, Noguchi H. BDNF prevents and reverses adult rat motor neuron degeneration and induces axonal outgrowth. Experimental Neurology. 1997;144(2):273-286. DOI: 10.1006/exnr.1996.6367
  116. 116. Chu T-H, Li S-Y, Guo A, Wong W-M, Yuan Q, Wu W. Implantation of neurotrophic factor-treated sensory nerve graft enhances survival and axonal regeneration of motoneurons after spinal root avulsion. Journal of Neuropathology and Experimental Neurology. 2009;68(1):94-101. DOI: 10.1097/NEN.0b013e31819344a9
  117. 117. Li L, Wu W, Lin LF, Lei M, Oppenheim RW, Houenou LJ. Rescue of adult mouse motoneurons from injury-induced cell death by glial cell line-derived neurotrophic factor. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(21):9771-9775
  118. 118. Noguchi T, Ohta S, Kakinoki R, et al. The neuroprotective effect of erythropoietin on spinal motor neurons after nerve root avulsion injury in rats. Restorative Neurology and Neuroscience. 2015;33(4):461-470. DOI: 10.3233/RNN-140481
  119. 119. Chew DJ, Carlstedt T, Shortland PJ. The effects of minocycline or riluzole treatment on spinal root avulsion-induced pain in adult rats. Journal of Pain, the Official Journal of the American Pain Society. 2014;15(6):664-675. DOI: 10.1016/j.jpain.2014.03.001
  120. 120. Kobayashi K, Imagama S, Ohgomori T, et al. Minocycline selectively inhibits M1 polarization of microglia. Cell Death & Disease. 2013;4:e525. DOI: 10.1038/cddis.2013.54
  121. 121. Nógrádi A, Vrbová G. The effect of riluzole treatment in rats on the survival of injured adult and grafted embryonic motoneurons. The European Journal of Neuroscience. 2001;13(1):113-118
  122. 122. Novikov LN, Novikova LN, Holmberg P, Kellerth J. Exogenous brain-derived neurotrophic factor regulates the synaptic composition of axonally lesioned and normal adult rat motoneurons. Neuroscience. 2000;100(1):171-181
  123. 123. Hadaczek P, Johnston L, Forsayeth J, Bankiewicz KS. Pharmacokinetics and bioactivity of glial cell line-derived factor (GDNF) and neurturin (NTN) infused into the rat brain. Neuropharmacology. 2010;58(7):1114-1121. DOI: 10.1016/j.neuropharm.2010.02.002
  124. 124. Sendtner M, Pei G, Beck M, Schweizer U, Wiese S. Developmental motoneuron cell death and neurotrophic factors. Cell and Tissue Research. 2000;301(1):71-84
  125. 125. Pajenda G, Hercher D, Márton G, et al. Spatiotemporally limited BDNF and GDNF overexpression rescues motoneurons destined to die and induces elongative axon growth. Experimental Neurology. 2014;261:367-376. DOI: 10.1016/j.expneurol.2014.05.019
  126. 126. Li H, Wong C, Li W, et al. Enhanced regeneration and functional recovery after spinal root avulsion by manipulation of the proteoglycan receptor PTPσ. Scientific Reports. 2015;5:14923. DOI: 10.1038/srep14923
  127. 127. Chu T-H, Wu W. Neurotrophic factor treatment after spinal root avulsion injury. Central Nervous System Agents in Medicinal Chemistry. 2009;9(1):40-55
  128. 128. Sakuma M, Gorski G, Sheu S-H, et al. Lack of motor recovery after prolonged denervation of the neuromuscular junction is not due to regenerative failure. The European Journal of Neuroscience. 2016;43(3):451-462. DOI: 10.1111/ejn.13059
  129. 129. Sandri M, Lin J, Handschin C, et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(44):16260-16265. DOI: 10.1073/pnas.0607795103
  130. 130. Brault JJ, Jespersen JG, Goldberg AL. Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. The Journal of Biological Chemistry. 2010;285(25):19460-19471. DOI: 10.1074/jbc.M110.113092
  131. 131. Lee D, Goldberg AL. SIRT1 protein, by blocking the activities of transcription factors FoxO1 and FoxO3, inhibits muscle atrophy and promotes muscle growth. The Journal of Biological Chemistry. 2013;288(42):30515-30526. DOI: 10.1074/jbc.M113.489716
  132. 132. Bahm J, El Kazzi W, Schuind F. Nerve transfers. Revue Médicale de Bruxelles. 2011;32(6 Suppl):S54-S57
  133. 133. Barbour J, Yee A, Kahn LC, Mackinnon SE. Supercharged end-to-side anterior interosseous to ulnar motor nerve transfer for intrinsic musculature reinnervation. Journal of Hand Surgery. 2012;37(10):2150-2159. DOI: 10.1016/j.jhsa.2012.07.022
  134. 134. Brown JM, Mackinnon SE. Nerve transfers in the forearm and hand. Hand Clinics. 2008;24(4):319-340. DOI: 10.1016/j.hcl.2008.08.002
  135. 135. Korus L, Ross DC, Doherty CD, Miller TA. Nerve transfers and neurotization in peripheral nerve injury, from surgery to rehabilitation. Journal of Neurology, Neurosurgery, and Psychiatry. 2016;87(2):188-197. DOI: 10.1136/jnnp-2015-310420
  136. 136. Garg R, Merrell GA, Hillstrom HJ, Wolfe SW. Comparison of nerve transfers and nerve grafting for traumatic upper plexus palsy: A systematic review and analysis. The Journal of Bone and Joint Surgery. American Volume. 2011;93(9):819-829. DOI: 10.2106/JBJS.I.01602
  137. 137. Adams V. Electromyostimulation to fight atrophy and to build muscle: Facts and numbers. Journal of Cachexia, Sarcopenia and Muscle. 2018;9(4):631-634. DOI: 10.1002/jcsm.12332
  138. 138. Bueno CR de S, Pereira M, Favaretto IA, et al. Electrical stimulation attenuates morphological alterations and prevents atrophy of the denervated cranial tibial muscle. Einstein (Sao Paulo, Braz) 2017;15(1):71-76. DOI: 10.1590/S1679-45082017AO3808
  139. 139. Elzinga K, Tyreman N, Ladak A, Savaryn B, Olson J, Gordon T. Brief electrical stimulation improves nerve regeneration after delayed repair in Sprague Dawley rats. Experimental Neurology. 2015;269:142-153. DOI: 10.1016/j.expneurol.2015.03.022
  140. 140. Su H, Zhang W, Yang X, et al. Neural progenitor cells generate motoneuron-like cells to form functional connections with target muscles after transplantation into the musculocutaneous nerve. Cell Transplantation. 2012;21(12):2651-2663. DOI: 10.3727/096368912X654975
  141. 141. Gu S, Shen Y, Xu W, et al. Application of fetal neural stem cells transplantation in delaying denervated muscle atrophy in rats with peripheral nerve injury. Microsurgery. 2010;30(4):266-274. DOI: 10.1002/micr.20722
  142. 142. Ruven C, Li W, Li H, Wong W-M, Wu W. Transplantation of embryonic spinal cord derived cells helps to prevent muscle atrophy after peripheral nerve injury. International Journal of Molecular Sciences. 2017;18(3): 511-535. DOI: 10.3390/ijms18030511
  143. 143. Pajer K, Nemes C, Berzsenyi S, et al. Grafted murine induced pluripotent stem cells prevent death of injured rat motoneurons otherwise destined to die. Experimental Neurology. 2015;269:188-201. DOI: 10.1016/j.expneurol.2015.03.031
  144. 144. Fujimoto Y, Abematsu M, Falk A, et al. Treatment of a mouse model of spinal cord injury by transplantation of human induced pluripotent stem cell-derived long-term self-renewing neuroepithelial-like stem cells. Stem Cells (Dayt., Ohio). 2012;30(6):1163-1173. DOI: 10.1002/stem.1083
  145. 145. Oda H, Ohta S, Ikeguchi R, et al. Pretreatment of nerve grafts with resveratrol improves axonal regeneration following replantation surgery for nerve root avulsion injury in rats. Restorative Neurology and Neuroscience. 2018;36(5):647-658. DOI: 10.3233/RNN-180844
  146. 146. Fang X-Y, Zhang W-M, Zhang C-F, et al. Lithium accelerates functional motor recovery by improving remyelination of regenerating axons following ventral root avulsion and reimplantation. Neuroscience. 2016;329:213-225. DOI: 10.1016/j.neuroscience.2016.05.010
  147. 147. Fu R, Tang Y, Ling Z-M, et al. Lithium enhances survival and regrowth of spinal motoneurons after ventral root avulsion. BMC Neuroscience. 2014;15:84. DOI: 10.1186/1471-2202-15-84
  148. 148. Udina E, Ceballos D, Verdú E, Gold BG, Navarro X. Bimodal dose-dependence of FK506 on the rate of axonal regeneration in mouse peripheral nerve. Muscle & Nerve. 2002;26(3):348-355. DOI: 10.1002/mus.10195
  149. 149. Labroo P, Ho S, Sant H, Shea J, Gale BK, Agarwal J. Controlled delivery of FK506 to improve nerve regeneration. Shock (Augusta, Ga.). 2016;46(3 Suppl 1):154-159. DOI: 10.1097/SHK.0000000000000628
  150. 150. Labroo P, Shea J, Sant H, Gale B, Agarwal J. Effect of combining FK506 and neurotrophins on neurite branching and elongation. Muscle & Nerve. 2017;55(4):570-581. DOI: 10.1002/mus.25370
  151. 151. Sugawara T, Itoh Y, Mizoi K. Immunosuppressants promote adult dorsal root regeneration into the spinal cord. Neuroreport. 1999;10(18):3949-3953
  152. 152. Sun HH, Saheb-Al-Zamani M, Yan Y, Hunter DA, Mackinnon SE, Johnson PJ. Geldanamycin accelerated peripheral nerve regeneration in comparison to FK-506 in vivo. Neuroscience. 2012;223:114-123. DOI: 10.1016/j.neuroscience.2012.07.026
  153. 153. Sano M. Radicicol and geldanamycin prevent neurotoxic effects of anti-cancer drugs on cultured embryonic sensory neurons. Neuropharmacology. 2001;40(7):947-953
  154. 154. Romeo-Guitart D, Forés J, Navarro X, Casas C. Boosted regeneration and reduced Denervated muscle atrophy by NeuroHeal in a pre-clinical model of lumbar root avulsion with delayed Reimplantation. Scientific Reports. 2017;7(1):12028. DOI: 10.1038/s41598-017-11086-3
  155. 155. Zhang C-G, Welin D, Novikov L, Kellerth J-O, Wiberg M, Hart AM. Motorneuron protection by N-acetyl-cysteine after ventral root avulsion and ventral rhizotomy. British Journal of Plastic Surgery. 2005;58(6):765-773. DOI: 10.1016/j.bjps.2005.04.012
  156. 156. Scorisa JM, Zanon RG, Freria CM, de Oliveira ALR. Glatiramer acetate positively influences spinal motoneuron survival and synaptic plasticity after ventral root avulsion. Neuroscience Letters. 2009;451(1):34-39. DOI: 10.1016/j.neulet.2008.12.017
  157. 157. Dyer AM, Smith A. Riluzole 5 mg/mL oral suspension: For optimized drug delivery in amyotrophic lateral sclerosis. Drug Design, Development and Therapy. 2017;11:59-64. DOI: 10.2147/DDDT.S123776
  158. 158. Fukumoto T, Morinobu S, Okamoto Y, Kagaya A, Yamawaki S. Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology. 2001;158(1):100-106. DOI: 10.1007/s002130100871
  159. 159. Hoang TX, Akhavan M, Wu J, Havton LA. Minocycline protects motor but not autonomic neurons after cauda equina injury. Experimental Brain Research. 2008;189(1):71-77. DOI: 10.1007/s00221-008-1398-5
  160. 160. Bowes AL, Yip PK. Modulating inflammatory cell responses to spinal cord injury: All in good time. Journal of Neurotrauma. 2014;31(21):1753-1766. DOI: 10.1089/neu.2014.3429
  161. 161. Faizul HG, Wutian W, Jafri Malin A. Histological analysis of motor neuron survival and microglial inhibition after nerve root avulsion treated with nerve graft implantation and minocycline: An experimental study. Sains Malaysiana;45(11):1641-1648
  162. 162. Tanaka T, Murakami K, Bando Y, Yoshida S. Minocycline reduces remyelination by suppressing ciliary neurotrophic factor expression after cuprizone-induced demyelination. Journal of Neurochemistry. 2013;127(2):259-270. DOI: 10.1111/jnc.12289
  163. 163. Yune TY, Lee JY, Jung GY, et al. Minocycline alleviates death of oligodendrocytes by inhibiting pro-nerve growth factor production in microglia after spinal cord injury. Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2007;27(29):7751-7761. DOI: 10.1523/JNEUROSCI.1661-07.2007
  164. 164. Pinkernelle J, Fansa H, Ebmeyer U, Keilhoff G. Prolonged minocycline treatment impairs motor neuronal survival and glial function in organotypic rat spinal cord cultures. PLoS One. 2013;8(8):e73422. DOI: 10.1371/journal.pone.0073422
  165. 165. Buemi M, Cavallaro E, Floccari F, et al. The pleiotropic effects of erythropoietin in the central nervous system. Journal of Neuropathology and Experimental Neurology. 2003;62(3):228-236
  166. 166. Kast RE, Altschuler EL. Consideration of acamprosate for treatment of amyotrophic lateral sclerosis. Medical Hypotheses. 2007;69(4):836-837. DOI: 10.1016/j.mehy.2007.01.072
  167. 167. Man AJ, Leach JK, Bannerman P. Redirection of neurite outgrowth by coupling chondroitin sulfate proteoglycans to polymer membranes. Annals of Biomedical Engineering. 2014;42(6):1271-1281. DOI: 10.1007/s10439-014-0991-y
  168. 168. Rodrigues Hell RC, Silva Costa MM, Goes AM, Oliveira ALR. Local injection of BDNF producing mesenchymal stem cells increases neuronal survival and synaptic stability following ventral root avulsion. Neurobiology of Disease. 2009;33(2):290-300. DOI: 10.1016/j.nbd.2008.10.017
  169. 169. Spejo AB, Carvalho JL, Goes AM, Oliveira ALR. Neuroprotective effects of mesenchymal stem cells on spinal motoneurons following ventral root axotomy: Synapse stability and axonal regeneration. Neuroscience. 2013;250:715-732. DOI: 10.1016/j.neuroscience. 2013.07.043
  170. 170. Torres-Espín A, Corona-Quintanilla DL, Forés J, et al. Neuroprotection and axonal regeneration after lumbar ventral root avulsion by re-implantation and mesenchymal stem cells transplant combined therapy. Neurother J Am Soc Exp Neurother. 2013;10(2):354-368. DOI: 10.1007/s13311-013-0178-5
  171. 171. Goméz VM, Averill S, King V, et al. Transplantation of olfactory ensheathing cells fails to promote significant axonal regeneration from dorsal roots into the rat cervical cord. Journal of Neurocytology. 2003;32(1):53-70
  172. 172. Barbizan R, Castro MV, Ferreira RS, Barraviera B, Oliveira ALR. Long-term spinal ventral root reimplantation, but not bone marrow mononuclear cell treatment, positively influences ultrastructural synapse recovery and motor axonal regrowth. International Journal of Molecular Sciences. 2014;15(11):19535-19551. DOI: 10.3390/ijms151119535
  173. 173. Konig N, Trolle C, Kapuralin K, et al. Murine neural crest stem cells and embryonic stem cell-derived neuron precursors survive and differentiate after transplantation in a model of dorsal root avulsion. Journal of Tissue Engineering and Regenerative Medicine. 2017;11(1):129-137. DOI: 10.1002/term.1893
  174. 174. Chen L, Lu L, Meng X, Chen D, Zhang Z, Yang F. Reimplantation combined with transplantation of transgenic neural stem cells for treatment of brachial plexus root avulsion. Chinese Journal of Traumatology—Zhonghua Chuang Shang Za Zhi. 2008;11(5):267-273
  175. 175. Tomita K, Hata Y, Kubo T, Fujiwara T, Yano K, Hosokawa K. Effects of the in vivo predegenerated nerve graft on early Schwann cell migration: Quantitative analysis using S100-GFP mice. Neuroscience Letters. 2009;461(1):36-40. DOI: 10.1016/j.neulet.2009.05.075
  176. 176. Danielsen N, Kerns JM, Holmquist B, Zhao Q, Lundborg G, Kanje M. Pre-degenerated nerve grafts enhance regeneration by shortening the initial delay period. Brain Research. 1994;666(2):250-254
  177. 177. Keilhoff G, Fansa H, Schneider W, Wolf G. In vivo predegeneration of peripheral nerves: An effective technique to obtain activated Schwann cells for nerve conduits. Journal of Neuroscience Methods. 1999;89(1):17-24
  178. 178. Carbonetto S. Facilitatory and inhibitory effects of glial cells and extracellular matrix in axonal regeneration. Current Opinion in Neurobiology. 1991;1(3):407-413
  179. 179. Höke A, Gordon T, Zochodne DW, Sulaiman OAR. A decline in glial cell-line-derived neurotrophic factor expression is associated with impaired regeneration after long-term Schwann cell denervation. Experimental Neurology. 2002;173(1):77-85. DOI: 10.1006/exnr.2001.7826
  180. 180. de Vries J, Menovsky T, van Gulik S, Wesseling P. Histological effects of fibrin glue on nervous tissue: A safety study in rats. Surgical Neurology. 2002;57(6):415-422; discussion 422
  181. 181. Kalsi P, Thom M, Choi D. Histological effects of fibrin glue and synthetic tissue glues on the spinal cord: Are they safe to use? British Journal of Neurosurgery. 2017;31(6):695-700. DOI: 10.1080/02688697.2017.1359491
  182. 182. Lemaire SA, Ochoa LN, Conklin LD, et al. Nerve and conduction tissue injury caused by contact with BioGlue. The Journal of Surgical Research. 2007;143(2):286-293. DOI: 10.1016/j.jss.2006.10.014
  183. 183. Barbizan R, Castro MV, Rodrigues AC, Barraviera B, Ferreira RS, Oliveira ALR. Motor recovery and synaptic preservation after ventral root avulsion and repair with a fibrin sealant derived from snake venom. PLoS One. 2013;8(5):e63260. DOI: 10.1371/journal.pone.0063260
  184. 184. Vidigal de Castro M, Barbizan R, Seabra Ferreira R, Barraviera B. Leite Rodrigues de Oliveira a. Direct spinal ventral root repair following avulsion: Effectiveness of a new heterologous fibrin sealant on Motoneuron survival and regeneration. Neural Plasticity. 2016;2932784:2016. DOI: 10.1155/2016/2932784
  185. 185. Wu J-C, Huang W-C, Huang M-C, et al. A novel strategy for repairing preganglionic cervical root avulsion in brachial plexus injury by sural nerve grafting. Journal of Neurosurgery. 2009;110(4):775-785. DOI: 10.3171/2008.8.JNS08328
  186. 186. Lin MY, Manzano G, Gupta R. Nerve allografts and conduits in peripheral nerve repair. Hand Clinics. 2013;29(3):331-348. DOI: 10.1016/j.hcl.2013.04.003
  187. 187. Magaz A, Faroni A, Gough JE, Reid AJ, Li X, Blaker JJ. Bioactive silk-based nerve guidance conduits for augmenting peripheral nerve repair. Advanced Healthcare Materials. 2018;7(23):e1800308. DOI: 10.1002/adhm.201800308
  188. 188. Tang X-Q, Cai J, Nelson KD, Peng X-J, Smith GM. Functional repair after dorsal root rhizotomy using nerve conduits and neurotrophic molecules. The European Journal of Neuroscience. 2004;20(5):1211-1218. DOI: 10.1111/j.1460-9568.2004.03595.x
  189. 189. Grahn PJ, Vaishya S, Knight AM, et al. Implantation of cauda equina nerve roots through a biodegradable scaffold at the conus medullaris in rat. Spine Journal: Official Journal of the North American Spine Society. 2014;14(9):2172-2177. DOI: 10.1016/j.spinee.2014.01.059
  190. 190. Safa B, Buncke G. Autograft substitutes: Conduits and processed nerve allografts. Hand Clinics. 2016;32(2):127-140. DOI: 10.1016/j.hcl.2015.12.012
  191. 191. Terris DJ, Toft KM, Moir M, Lum J, Wang M. Brain-derived neurotrophic factor-enriched collagen tubule as a substitute for autologous nerve grafts. Archives of Otolaryngology—Head & Neck Surgery. 2001;127(3):294-298
  192. 192. Kline DG, Donner TR, Happel L, Smith B, Richter HP. Intraforaminal repair of plexus spinal nerves by a posterior approach: An experimental study. Journal of Neurosurgery. 1992;76(3):459-470. DOI: 10.3171/jns.1992.76.3.0459
  193. 193. Camp SJ, Carlstedt T, Casey ATH. The lateral approach to intraspinal reimplantation of the brachial plexus: A technical note. Journal of Bone and Joint Surgery. British Volume (London). 2010;92(7):975-979. DOI: 10.1302/0301-620X.92B7.23778
  194. 194. Fournier HD, Mercier P, Menei P. Repair of avulsed ventral nerve roots by direct ventral intraspinal implantation after brachial plexus injury. Hand Clinics. 2005;21(1):109-118. DOI: 10.1016/j.hcl.2004.09.001
  195. 195. Fournier HD, Mercier P, Menei P. Lateral interscalenic multilevel oblique corpectomies to repair ventral root avulsions after brachial plexus injury in humans: Anatomical study and first clinical experience. Journal of Neurosurgery. 2001;95(2 Suppl):202-207
  196. 196. Dubuisson AS, Kline DG, Weinshel SS. Posterior subscapular approach to the brachial plexus. Report of 102 patients. Journal of Neurosurgery. 1993;79(3):319-330. DOI: 10.3171/jns.1993.79.3.0319
  197. 197. Maldonado AA, Kircher MF, Spinner RJ, Bishop AT, Shin AY. Free functioning gracilis muscle transfer with and without simultaneous intercostal nerve transfer to musculocutaneous nerve for restoration of elbow flexion after traumatic adult brachial pan-plexus injury. Journal of Hand Surgery. 2017;42(4):293.e1-293.e7. DOI: 10.1016/j.jhsa.2017.01.014
  198. 198. Gu Y, Xu J, Chen L, Wang H, Hu S. Long term outcome of contralateral C7 transfer: A report of 32 cases. Chinese Medical Journal. 2002;115(6):866-868
  199. 199. Wang S, Yiu H-W, Li P, Li Y, Wang H, Pan Y. Contralateral C7 nerve root transfer to neurotize the upper trunk via a modified prespinal route in repair of brachial plexus avulsion injury. Microsurgery. 2012;32(3):183-188. DOI: 10.1002/micr.20963
  200. 200. Hoang TX, Havton LA. Novel repair strategies to restore bladder function following cauda equina/conus medullaris injuries. Progress in Brain Research. 2006;152:195-204. DOI: 10.1016/S0079-6123(05)52012-0
  201. 201. Fournier HD, Menei P, Khalifa R, Mercier P. Ideal intraspinal implantation site for the repair of ventral root avulsion after brachial plexus injury in humans. A preliminary anatomical study. Surgical and Radiologic Anatomy. 2001;23(3):191-195
  202. 202. Sáiz-Sapena N, Vanaclocha V, Insausti R, Idoate M. Dorsal root repair by means of an autologous nerve graft: Experimental study in the rat. Acta Neurochirurgica. 1997;139(8):780-786
  203. 203. Cheah M, Fawcett JW, Andrews MR. Dorsal root ganglion injection and dorsal root crush injury as a model for sensory axon regeneration. Journal of Visualized Experiments. 2017;123:1-7. DOI: 10.3791/55535
  204. 204. George B, Gauthier N, Lot G. Multisegmental cervical spondylotic myelopathy and radiculopathy treated by multilevel oblique corpectomies without fusion. Neurosurgery. 1999;44(1):81-90
  205. 205. null G, null L. Surgical treatment of dumbbell neurinomas of the cervical spine. Critical Reviews in Neurosurgery. 1999;9(3):156-160
  206. 206. Bayerl SH, Pöhlmann F, Finger T, Prinz V, Vajkoczy P. Two-level cervical corpectomy-long-term follow-up reveals the high rate of material failure in patients, who received an anterior approach only. Neurosurgical Review. 2018; Jun:1-8. DOI: 10.1007/s10143-018-0993-6
  207. 207. Holtzer CAJ, Marani E, van Dijk GJ, Thomeer RTWM. Repair of ventral root avulsion using autologous nerve grafts in cats. Journal of the Peripheral Nervous System. 2003;8(1):17-22
  208. 208. Hoffmann CF, Thomeer RT, Marani E. Ventral root avulsions of the cat spinal cord at the brachial plexus level (cervical 7). European Journal of Morphology. 1990;28(2–4):418-429
  209. 209. Amr SM, Moharram AN. Repair of brachial plexus lesions by end-to-side side-to-side grafting neurorrhaphy: Experience based on 11 cases. Microsurgery. 2005;25(2):126-146. DOI: 10.1002/micr.20036

Written By

Vicente Vanaclocha-Vanaclocha, Nieves Saiz-Sapena, José María Ortiz-Criado and Leyre Vanaclocha

Reviewed: 06 November 2018 Published: 08 April 2019