Clinical and neurobiological advances in promoting regeneration of the ventral root avulsion lesion

Abstract

Root avulsions due to traction to the brachial plexus causes complete and permanent loss of function. Until fairly recent, such lesions were considered impossible to repair. Here we review clinical repair strategies and current progress in experimental ventral root avulsion lesions. The current gold standard in patients with a root avulsion is nerve transfer, whereas reimplantation of the avulsed root into the spinal cord has been performed in a limited number of cases. These neurosurgical repair strategies have significant benefit for the patient but functional recovery remains incomplete. Developing new ways to improve the functional outcome of neurosurgical repair is therefore essential. In the laboratory, the molecular and cellular changes following ventral root avulsion and the efficacy of intervention strategies have been studied at the level of spinal motoneurons, the ventral spinal root and peripheral nerve, and the skeletal muscle. We present an overview of cell-based pharmacological and neurotrophic factor treatment approaches that have been applied in combination with surgical reimplantation. These interventions all demonstrate neuroprotective effects on avulsed motoneurons, often accompanied with various degrees of axonal regeneration. However, effects on survival are usually transient and robust axon regeneration over long distances has as yet not been achieved. Key future areas of research include finding ways to further extend the post-lesion survival period of motoneurons, the identification of neuron-intrinsic factors which can promote persistent and long-distance axon regeneration, and finally prolonging the pro-regenerative state of Schwann cells in the distal nerve.

Nerve Root Reimplantation in Brachial Plexus Injuries

“…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 C 8 and T 1 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 C 5 and T 1 sensory recovery can in part be due to overlapping sensory covering from nearby dermatomes (C 4 for C 5 and T 2 for T 1 ) [32,45].…”

“…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].…”

“…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][86][87], and in any case only proximal limb muscle recovery is seen [86][87][88][89].…”

“…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].…”

“…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].…”