Do motoneurons survive root avulsion?

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Do motoneurons

survive root avulsion?

C.F.E. Hoffmann’12 and R.T.W.M. Thomeer’ 1 Department of Neurosurgery, University Hospital, and ’ Neworegulation Group and Physiolom, Leiden (The Netherlana%)

Traction injuries to the human brachial plexus can result in widespread lesions, affecting roots, spinal nerves, primary trunks, divisions, fasciculi, and peripheral nerves. Unlike most interruptions of the extravertebral part of the plexus, root avulsions from the spinal cord arc beyond surgical repair and lead to permanent disabling condition

PI* The peripheral nervous system (PNS) possesses an intrinsic capacity to regenerate after injury. The events following interruption of a peripheral nerve fiber have been studied extensively. Initially, axons and myelin in the distal nerve segment degcncrate (wallerian degeneration), but Schwann cells with their surrounding basal lamina persist [2] and proliferate within these sheets to form longitudinal columns called bands of Bungner [3]. Regeneration starts at the proximal stump with the formation of some new axonal processes called regenerative sprouts. Generally, only one sprout survives and elongates within these columns. The axon becomes secondarily myelinated by Schwann cells. Besides mechanical support to regrowing axons, neurotrophic factors are indispensable for both extended elongation and guidance towards their original targets. The degree of functional recovery depends primarily on the quality of the anatomic apposition of the severed parts, or the graft bridging a nerve gap, but other factors like delay of surgical repair and tissue vitality may influence the final result as well. After an injury to the adult mammalian central nervous system (CNS), interrupted libres do not regrow and elongate by more than an initial sprout of about 1 mm. This phenomenon was described by Ramon y Cajal as early as 1928 [4], and was called abortive sprouting. In recent decades attempts have been made to implant embryonic cord grafts into the adult host spinal cord. The embryonic grafts survived and elongated into the host neuropil, but the neosynaptogenesis indispcnsablc for functional recovery was not found. This kind of experiments with embryonic implants has, in our opinion, been erroneously characterized as regenerative rather than Correspo/tdence to: Prof. Dr. R.T.W.M. Neurosurgcty, h’ethcrlands.

University

I lospital,

Thomeer, Department of P.0. Box 9MJO,2300 RC Iridcn,‘Ihc

generative studies. Another approach used to improve the poor axonal regrowth was to apply PNS grafts in the CNS lesion area. The results showed that transected CNS axons elongate some millimeters into the PNS implant and become myelinated again [5,6]. However, no evidence of functional regeneration in the CNS has been reported so far. Although located within the CNS, anterior horn cells functionally belong to the PNS and mediate axoaal repair in peripheral nerve injuries. From a clinical interest we are performing experimental studies to investigate possible regeneration after root avulsion. In our view, the primary question to bc answered is the following do motoncurons survive such a proximal lesion or, is there a critical length of the interrupted axon to remain in contact with the motoneuron in order to survive? We investigated the neuronal reaction within the cat spinal cord after selective avulsion of the seventh cervical ventral after various survival times [7] and compared the results with those of a sharp transection of the ventral root as close as possible to the spinal cord (unpublished data). Thirty days after uvuisiotz, no difference in the total cell number was found between the neurons in the ventral horn on the avulsed side and those on the undamaged side. However, 90 days after avulsion we saw a significant dccrcasc in the number of neurons (alpha, gamma, and intcrmcdiatc types, in invariable proportions) in the ventral horn on the avulsed side. Actually, only few motoneurons wcrc still prcscnt. Thirty and 90 days after frmrsecGo/l, there was no difference in the total number of cells in the ventral horn compared with the intact side. Where did the axons rupture at avulsion? Our observations, made with the operation microscope, led us to believe that some rootlcts were torn from the cord, leaving a small hole in the latter, and others ruptured more distally, leaving a short stump attached to the cord. The contention that at least some axons rupture within the cord is further supported by the finding of terminal clubs in some of the axonal pathways in the white matter betwccn the anterior horn and the pia mater until 30 days after avulsion 181.Terminal clubs or retraction balls are enlargements at the site of the axonal injury in which

axoplasmic organelles accumulate. It has been conclusively shown that the central-peripheral nervous system transitional region is juxtamedullary localized within the rootlets. Each such transitional region entity can be divided into an axial cone-shaped CNS compartment and a surrounding PNS compartment [9]. The PNS compartment contains Schwann cells, fibroblasts, and pericytes, the CNS compartment oligodendrocytes, astrocytes, and microglia. This means that the ventral horn motoneurons, including a short axon segment (l-4 mm), are situated within the CNS and have both morphological and biochemical CNS characteristics. Perhaps more strongly than the length of the remaining axon, the site of rupture of the axon, either within or outside the CNS, determines whether the perikaryon will survive and/or induce axonal regeneration. This hypothesis might explain the difference in cell death between the effect of an avulsion and a transection. A transection made as close as possible to the spinal cord, is a PNS lesion not accompanied by neuronal death. The avulsion is a CNS lesion but in our study not all neurons had died 90 days after avulsion. The different site of rupture, within or outside the CNS, might explain this finding, but surviving motoneurons might belong to the adjacent segment cluster as well. It has been claimed that the CNS neurons have an intrinsic regenerative power [4,10], facilitated by a number of identified neurotrophic factors such as nerve growth factor (NGF), brain-derived ncurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and fibroblast growth factor (FGF). This view is supported by the finding of increase of neurotrophic activities at central lesion sites. Environmental factors have been blamed for the failure of actual regeneration in the CNS: in the first place the formation of connective scar tissue, containing fibroblasts and a dense collagcnous matrix, which prevents axonal elongation. In the second place growth-inhi-

biting factors have been blamed. Recently, membrane proteins were localized selectively in oligodendrocytes and CNS myelin, which exert a powerful inhibitory effect on neurite growth [ll]. The cell death occurring after avulsion of the ventral root seems to preclude spontaneous regeneration. Reimplantation of the avulsed ventral root or a PNS graft into the spinal cord at the place where the ventral root was avulsed might help the axonal sprouts of the avulsed motoneurons to regrow to their original targets. The damaged axons are offered a PNS environment, including Schwann cell mediated growth factors, to overcome the inhibitory factors in the CNS. The effects of reimplantation of the ventral rootlets into the anterior horn, immediately after avulsion, are subject of ongoing study.

References 1991; 93: 3-11. 1 Thomeer RlWM. Clin Neurol Neurosurg IIJ, Spencer PS. J Neurocytol 1978; 7: X5-569. 2 Weinberger 3 Thomas PK. In: Bellairs R, Gray EG (eds): Essays on the Nervous System. London/New York: Oxford Univ. Press, 1974, pp 44-70. 4 Ramon Y Cajal S. London: Oxford Univ. Press, 1928. 5 Kao CC, Chang LW, Bloodworth JR J Neurosurg 1977; 46: 757-766. JIIC, De Beer FC, Marani E, Thomeer RTWM. In: 6 Voormolen Cohadon F, Lobo Antuncs J (eds.), Recovery of Function in the Nervous System. Padova: Liviana Press, 1988: 107-115. CFE, Thomeer RTWM, Marani E. Eur. J. Morphol. 7 IIoffmann 1990; 28: 418429. CFE, Thomeer RTWM, Marani E. Restor Neurol Neu8 Iloffmann rosci 1991; 2: 205-210. 0. In Dyck PJ et al. (eds): 9 Erthold CII, Carlstedt T, Corneliuson Peripheral Neuropathology. Philadelphia: Saunders, 1984: lS6-170. from injured neurons in the adult 10 Guayo AJ. Axonal regeneration mammalian central nervous system. In: Cotman CW, (ed): Synaptic Plasticity. New York: Guilford Press, 1985: 457484. inhibitors of neurite growth and 11 Schwab ME. Myelin-associated regcncration in the CNS. Trends Neurosci 1990; 13:452--156.