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].

Soon after avulsion anterior horn motor neurons (MN) and sensory neurons at the dorsal root ganglion (DRG) undergo apoptosis [8–17]. 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

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

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 [31–33]. 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 [34–36]. Acellular conduits have also been used, but

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

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

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

cells that secrete neurotrophic factors (NFs) with higher regeneration abilities [47].

animals and in human beings with partial recovery [26, 27].

the regeneration does not grow further than 2 cm [37, 38].

pain [21–24].

46 Treatment of Brachial Plexus Injuries

1.1. Historical background

regenerating capacities.

2. Pathophysiology

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, 52–55]. 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) [57–59] and oligodendrocytes (myelin protein [60–62] 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) [79–81].

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 [10–13, 23, 67, 68, 70, 82–84]. 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, 85–87], and in any case only proximal limb muscle recovery is seen [86–89]. 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].

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

Nerve Root Reimplantation in Brachial Plexus Injuries http://dx.doi.org/10.5772/intechopen.82431 49

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

NF administration improves MN survival as well as synaptic and axonal regrowth [87, 112–115] improving the NR reimplantation results. NFs enhance Schwann cell migration, axonal regeneration and myelination [8, 16, 69, 93, 105, 116–120] and delay MN apoptosis—by 6 weeks 80–90% of them are still alive [8, 69, 116, 118–121]. 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

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 [129–131], nerve transfers from neighboring functioning nerves [132–136], direct electrical stimulation of the affected muscles [137–139] and neuronal transplantation inside the denervated muscle [20, 140–142]. 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

3. Pharmacological aids to enhance regeneration after nerve root

reimplantation [26].

reimplantation

and cell-derived products (Table 1).

action, thus facilitating axonal regeneration [126].

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, 91–93]. 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, 101–103]. 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].
