Peripheral Nerve Trunks Research Articles

Basic science of peripheral nerve repair: Wallerian degeneration/growth cones

Trauma to a peripheral nerve trunk is a complex injury because it involves not only repair processes locally at the peripheral level, but it also engages repair and compensation mechanisms at central levels. The main actor is the fascinating and unique neuron with its supporting cells, which consist mainly of Schwann cells. In the neuron and in the Schwann cells, intracellular signaling mechanisms are initiated by the peripheral nerve injury and aim to turn the intracellular processes into a regenerative and proliferative state. The intracellular signaling mechanism is called signal transduction and works along the entire neuron, including the intracellular axonal transport system. A very delicate interaction occurs between the growth cones formed by the distal tip of the outgrowing axons and the environment into which the axons grow. A large number of changes occur in this environment due to the process of Wallerian degeneration caused by the injury. A thorough knowledge of the cellular and molecular repair mechanisms after peripheral nerve injury is the basis on which we can build new research with the aim to improve results after this devastating injury, because there are limitations in the pure surgical treatment of peripheral injury.

Impairments in multibacillary leprosy; a study from Brazil

This is a retrospective cohort study of 103 multibacillary leprosy patients (18% BB, 48% BL and 34% LL) followed during and after treatment, in a tertiary referral centre with an outpatient clinic in an endemic area in Brazil, for an average period of 65 months since the start of multidrug therapy (24-dose MDT). The objective of the study was to identify the role of overt neuritis (presence of pain in a peripheral nerve trunk, with or without enlargement or neural function damage), in the development of impairments. They were evaluated using the World Health Organization disability grade before treatment, at the end of the treatment, and at the end of the follow-up period. Thirty-four percent of patients presented overt neuritis during MDT, and 45% had overt neuritis episodes during the follow-up period; the most commonly affected nerves were ulnar, fibular and posterior tibial nerves, and the neuritic episodes were carefully treated with steroid therapy and physiotherapy. Impairments were associated with: affected (painful and/or thick) nerves at diagnosis (P < 0.005); delay in diagnosis (P = 0.010); impairments already present at the start of treatment (P = 0.00041 at the end of MDT, and P = 0.000013 at the end of follow-up); occurrence of overt neuritis episodes during MDT (P = 0.0016) or the whole follow-up (P = 0.015). These data draw attention to the importance of early diagnosis and of good neurological examination throughout the follow-up, as well as suggest the importance of neuritis in the induction of impairments in multibacillary leprosy.

Nerve thickening in leprosy patients and risk of paralytic deformities: a field based study in Agra, India

This paper examines the extent of nerve thickening among leprosy patients detected in the field in Agra district. All the clinically diagnosed leprosy patients were examined in detailed for thickening of local cutaneous nerves and peripheral nerve trunks. In each case all the major nerve trunks in both upper and lower extremities, forehead and neck were examined for thickening. Nerve thickening was found in 94% of multibacillary (MB) patients and among 52% paucibacillary (PB) patients. Nerve thickening was found to be more in males, in prevalent cases than in new (untreated) cases and increased significantly with age and delay in diagnosis (P<0.001). Visible deformities of grade > or =2 were found in 10% (58/573) of the leprosy patients; paralytic deformity accounted for 78% (45/58). Claw hand alone or in combination was seen in 82% (37/45) of patients with paralytic deformities. Risk (odd ratio) for deformities was observed to be high (15-18 times) with increasing number of nerves among patients with neuritic leprosy but correlated with delay in diagnosis of over 5 years. Likewise, deformities were more often seen in those with skin lesions, provided they had > or =3 thickened nerves. Findings suggest that early detection and treatment is useful in preventing deformities.

The role of a barrier between two nerve fascicles in adjacency after transection and repair of a peripheral nerve trunk

Aberrant reinnervation of target organs caused by misdirected axonal growth at the repair site is a major reason for the poor functional outcome usually seen after peripheral nerve transection and repair. The following two studies investigate whether criss-crossing of regenerating rat sciatic nerve axons between tibial and peroneal nerve fascicles can be reduced by using a barrier at the coaption site. The left sciatic nerve was transected and repaired at mid-thigh as follows: epineural sutures (group A, A-II), fascicular repair of tibial and peroneal nerve fascicles (group B, B-II), fascicular repair of tibial and peroneal nerve fascicles separating the two fascicles with a pedicled fat flap (group C), Integra® (group D) or non-vascularized autologous fascia (group C-II). In the control groups E and D-II, only the left tibial fascicle was transected and repaired. Four and 5 months postoperatively, the outcome of regeneration was evaluated by histology, by retrograde tracing, and by assessment of the muscle force of the gastrocnemius and tibial anterior muscles. The tracing experiments showed that specificity of muscle reinnervation significantly improved when a barrier was employed, which significantly or clearly improved muscle twitch tension in groups C and D. However, muscle contraction force was not better when fascia was used as barrier. The histological picture indicated that this inferior result in group C-II was due to nerve compression caused by fibrotic scar tissue at the site of the fascia graft. Results of this study show that a pedicle fat flap and Integra® used as barrier significantly prevent aberrant reinnervation between two sutured nerve fascicles in adjacency resulting in improved motor recovery in rats. Non-vascularized autologous fascia however, reduces also criss-crossing of regenerating axons between the fascicles, but causes significant nerve compression.

Pure neuritic leprosy in India: an appraisal.

Pure neuritic leprosy (PNL) constitutes a significant proportion of all cases in India, however, this form of disease has not been fully recognized and investigated and there is little information in the existing literature. To study the epidemiological characteristics of PNL in India. A retrospective analysis of leprosy clinic records for the period 1993 to 2003 was undertaken. Detailed demographic profiles and clinical findings were noted from the predesigned clinic proforma. A slit-skin smear for acid-fast baclli (AFB) was done in all cases from the area of sensory loss. A skin biopsy was done from the area of sensory impairment to study histopathological changes. Further investigations such as nerve conduction velocity studies (NCV), fine needle aspiration cytology (FNAC), or nerve biopsy (superficial nerve twigs) were done if indicated in patients whenever there was difficulty in clinical diagnosis. Of the total 1542 leprosy patients seen over this period, 65 (4.2%) had PNL. Males were more commonly affected than females (2.6:1.). The majority of patients 40/65(61.5%) were aged between 15 and 35 yrs. Predominant presenting symptoms were paresthesia, pain, sensory/motor deficit, and trophic changes. A majority of the patients 39/65 (60.0%) presented with involvement of 2 or more nerves in the same extremity. Mononeuritis was seen in 26 (40%) patients. The nerves most often involved were the right ulnar nerve in the upper extremity, and the right common peroneal nerve in the lower limb. In general, the nerves of the upper extremity were more commonly involved than in the lower limbs (67 vs. 55). Motor deformities such as claw hand and foot drop were present in 13/75 (20%) and 7/65 (10.8%) patients, respectively. Slit-skin smears were negative in all patients, and skin histopathology from the area of sensory loss revealed non-specific inflammation in the dermis in a majority of patients, with perineural inflammation in a few. All patients were treated with multi-drug therapy (MDT); patients with >/=2 peripheral nerve trunk involvements were treated with WHO MDT MB regimen, while others were administered WHO MDT PB regimen. Follow-up for up to 2 yrs was available in only 32/65 (49.2%) patients, none of whom developed any skin lesions during this period. PNL is a distinct subset of disease frequently seen in India. There is need to pay more attention to this form of leprosy and diagnose and treat patients earlier to prevent deformities and sequelae of nerve damage.

Tricyclic antidepressants as long-acting local anesthetics

Amitriptyline, nortriptyline, imipramine, doxepin, desipramine, protriptyline, trimipramine, and maprotiline are tricyclic antidepressants (TCAs) used orally in treating major depressive disorders. Recent studies showed that amitriptyline is more potent in blocking the sciatic nerve functions in vivo by local injection than bupivacaine, a long-acting local anesthetic. We therefore tested whether various TCAs could likewise act as local anesthetics in vivo after single injection via the rat sciatic notch. The duration of complete sciatic nerve blockade by TCAs and the time to reach full recovery were measured with neurobehavioral assays and compared with results from bupivacaine. Amitriptyline, doxepin, and imipramine at 5mM elicited a longer complete sciatic nerve blockade than did bupivacaine at 15.4mM (0.5%), whereas trimipramine and desipramine at 5mM produced a shorter blockade. In contrast, nortriptyline, protriptyline, and maprotiline failed to elicit complete sciatic nerve blockade. Thus, TCAs have very different efficacy as local anesthetics in vivo. The duration of rat sciatic nerve blockade in vivo by TCAs is not well correlated with the 50% inhibitory concentration (IC50) of TCAs in blocking human cardiac Nav1.5 Na+ channels expressed in human embryonic kidney cells. With this in vitro expression system, TCAs appear more potent than bupivacaine as Na+ channel blockers in Nav1.5 Na+ channels. We suggest that the ability of TCAs to pass through various membrane barriers within peripheral nerve trunks is crucial to their local anesthetic efficacy in vivo. TCAs with a tertiary amine appear more effective in penetrating these membrane barriers than TCAs with a secondary amine.

Sensory perception in leprosy-neurophysiological correlates.

The loss of sensation in skin lesions, and in a palm or sole that has been innervated by peripheral nerve trunks, is characteristic of leprosy. Detection of early nerve trunk involvement depends on demonstrating sensory loss. Newer developments in neurological sciences have made fresh interpretations of the observed sensory abnormalities in leprosy-affected persons possible. Some of these observations are described in this review, and their implications discussed.

Activation of adenosine and P2Y receptors by ATP in human peripheral nerve.

Receptors for ATP in the peripheral nervous system may contribute to the transduction of sensory, including nociceptive, stimuli and are candidates in the pathogenesis of neuropathic pain. In a complex neural tissue, such as the human peripheral nerve trunk, ATP may activate P2X, P2Y, and adenosine receptors present on various cell types. Experiments were performed on segments of isolated human sural nerves. The experimental set-up enabled simultaneous recording of C fiber excitability, intracellular Ca(2+) ([Ca(2+)](i)) and extracellular K(+) activity (aK(e)). The increase in excitability of unmyelinated fibers seen during bath application of both ATP and adenosine was reversed to a reduction in axonal excitability in the presence of 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolol[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385), an antagonist of adenosine A2 receptors. The pharmacological profile of the axonal subexcitability indicates the presence and activation of adenosine A1 receptors. Intracellular Ca(2+) transients were observed during bath application of ATP but not of adenosine and were blocked by 2'-deoxy- N(6)-methyladenosine 3',5'-bisphosphate (MRS 2179), an antagonist at P2Y(1) receptors. K(+)-sensitive microelectrodes were used to search for a possible activation of P2X receptors by ATP. In isolated rat vagus nerve, activation of P2X receptors by alpha,beta-methylene-adenosine 5'-triphosphate (alpha,beta-meATP) and by diadenosine pentaphosphate (Ap5A) resulted in a rapid, transient rise in the extracellular K(+) activity. In contrast, in human nerve, application of P2X receptor agonists did not result in a detectable elevation of aK(e). The data suggest that ATP-induced changes in axonal excitability and of [Ca(2+)](i) result from activation of adenosine A2, A1 and P2Y nucleotide receptors in human nerve; a contribution of P2X receptors was not found with the methods used. It is suggested that antagonists of A2 receptors might suppress enhanced activity in human nociceptive afferent nerve fibers under conditions in which ATP and/or adenosine is released into the trunk of a human peripheral nerve.

Na x sodium channel is expressed in non-myelinating Schwann cells and alveolar type II cells in mice

Na x is an extracellular sodium-level-sensitive sodium channel expressed in the circumventricular organs in the brain, essential loci for the sodium-level homeostasis in body fluids. Here, we examined the localization of Na x throughout the visceral organs at the cellular level. In visceral organs including lung, heart, intestine, bladder, kidney and tongue, a subset of Schwann cells within the peripheral nerve trunks were highly positive for Na x. An electron microscopic study indicated that these Na x-positive cells were non-myelinating Schwann cells. In the lung, Na x-positive signals were also observed in the alveolar type II cells, which actively absorb sodium and water to aid gas exchange through the alveolar surface. It was thus suggested that the Na x sodium channel is involved in controlling the local extracellular sodium level through sodium absorption activity.

Enhancement of neurokinin A-induced smooth muscle contraction in human urinary bladder by mucosal removal and phosphoramidon: relationship to peptidase inhibition

Neurokinin A (NKA) is potent in contracting the human detrusor muscle. Here, we have investigated whether these contractile responses are influenced by the presence of the mucosa, by the peptidase inhibitor phosphoramidon or by possible modulators, prostaglandins and nitric oxide. Contractile responses to neurokinin A were unaffected by indomethacin or N-ω-nitro- l-arginine, but were significantly reduced in strips containing mucosa. Phosphoramidon, an inhibitor of neutral endopeptidase 24.11 (neprilysin, CD10), was ineffective at 10 μM, but at 100 μM, significant increase in the maximum response was achieved by neurokinin A in detrusor strips with and without mucosa. In immunohistochemical studies, neutral endopeptidase immunoreactivity occurred in peripheral nerve trunks in the detrusor and in a fibrous meshwork in the subepithelial lamina propria. Our data indicate that neutral endopeptidase is present in bladder mucosa and detrusor, and support the concept that this metalloprotease and/or related enzymes are important in regulating the actions of tachykinins.

Nerve and ganglion blood flow in diabetes: An appraisal

Vasa nervorum, the vascular supply to peripheral nerve trunks, and their associated cell bodies in ganglia have unique anatomical and physiological characteristics. Several different experimental approaches toward understanding the changes in vase nervorum following injury and disease have been used. Quantative techniques most widely employed have been microelectrode hydrogen clearance palarography and [14C]iodoantipyrine autoradiographic distribution, whereas estimates of red blood cell flux using a fiber-optic laser Doppler probe offer real time data at different sites along the nerve trunk. There are important caveats about the use of these techniques, their advantages, and their limitations. Reports of nerve blood flow require careful documentation of physiological variables, including mean arterial pressure and nerve temperature during the recordings. Several ischemic models of the peripheral nerve trunk have addressed the ischemic threshold below which axonal degeneration ensues (< 5ml/100 g/min). Following injury, rises in local blood flow reflect acitons of vasoactive peptides, nitric oxide, and the development of angiogenesis. In experimental diabetes, a large number of studies have documented reductions in nerve blood flow and tandem corrections of nerve blood flow and conduction slowing. A significant proportions, however, of the work can be criticized on the basis of methodology and interpretation. Similarly, not all work has confirmed that reductions of nerve blood flow are an invariable feature of experimental or human diabetic polyneuropathy. Therefore, while there is disagreement as to whether early declines in nerve blood flow "account" for diabetic polyneuropathy, there is unquestioned eveidence of early microangiopathy. Abnormalities of vase nervorum and micorvessels supplying ganglia at the very least develop parallel to and together with changes in neurons, Schwann cells, and axons.

Nerve regeneration through a healthy peripheral nerve trunk as a nerve conduit: a preliminary study of a new concept in peripheral nerve surgery.

The popularity of nerve conduits has increased recently due to the need for alternative nerve reconstruction techniques, obviating the harvest of nerve grafts. Based on ideas suggesting nerve tissue itself, which was the most physiologic environment for nerve regeneration, a study using 40 sciatic nerves of 20 rats was performed. The proximal stumps of transected peroneal nerves were sutured to the lateral wall of healthy tibial nerve trunks after removal of the epineurium. Twelve weeks later, tissue samples were taken from the anastomosis sites and from the levels above and below these sites. Configurations of fascicles were evaluated, and numbers of fibers were estimated. It was observed that the fibers of peroneal nerves regenerated into and through the tibial nerve trunk distally. This suggested that active regenerating fibers of a proximal stump of a nerve could regenerate and progress as a fascicular unit in optimum condition at the trunk of another healthy nerve. This preliminary study should stimulate further studies based on this new concept: that a nerve trunk can serve as the host for the regenerating fibers of another nerve.

Do Denervated Peripheral Nerve Trunks Become Ischemic? The Impact of Chronic Denervation on Vasa Nervorum

The long-term relationship between the peripheral nerve trunk and its vascular supply, the vasa nervorum, has not been considered in the context of denervation and regeneration. While the microvessels of peripheral nerve are not thought to influence Wallerian degeneration itself, in this work we explored how vasa nervorum respond to denervation of the nerve trunk. Our hypotheses were that the presence of axons had a significant impact on the vasa nervorum and that the absence of reinnervation might eventually lead to an unfavorable ischemic regenerative microenvironment. We studied rat sciatic nerve trunks for up to 6 months following transection and either prevented regeneration or allowed it to proceed. Vasa nervorum were studied in several ways: (i) measurements of local endoneurial blood flow using microelectrode hydrogen clearance polarography; (ii) measurements of erythrocyte flux (flow) in the extrinsic nerve plexus using laser Doppler flowmetry; (iii) India ink perfusion of microvessels in unfixed nerve; (iv) mRNA expression of vascular endothelial growth factor (VEGF) using reverse transcription polymerase chain reaction. Early after injury, there were rises in endoneurial and extrinsic flow, microvessel numbers, and VEGF mRNA expression. Angiogenesis was apparently confined to the epineurial and perineurial compartments. Later, however, there were substantial declines in flow observed in long-term (6-month) denervated sciatic nerve trunks associated with declines in the caliber of new microvessels. Reinnervated sciatic nerves had restored endoneurial blood flow. The findings confirm important relationships between axon presence and local blood flow. Angiogenesis is a feature of the injured peripheral nerve, but long term denervated nerve trunks have declines of flow despite retaining new microvessels.

Diabetes causes an early reduction in autonomic ganglion blood flow in rats

Impaired blood flow to peripheral nerve trunks makes a major contribution to the neuropathic complications of diabetes mellitus. Comparatively little attention has been paid to perfusion abnormalities for the cell bodies of origin of the autonomic and sensory nerves, although they are severely affected in diabetic neuropathy. The aim was to examine the time course of changes in superior cervical ganglion (SCG) perfusion in streptozotocin-induced diabetic rats. Ganglion blood flow, measured by hydrogen clearance microelectrode polarography, was approximately 70 ml min −1 100 g −1. One week of diabetes caused a 46% perfusion deficit, which was maintained (54%) over 24 weeks. Thus, an early, profound, and long-lived reduction in ganglion perfusion may deleteriously affect neural cell body function and could contribute to autonomic neuropathy.

ATP affects both axons and Schwann cells of unmyelinated C fibres

Recent studies indicate that effects of ATP on unmyelinated afferent nerve fibres contribute to the transduction of nociceptive and non-nociceptive stimuli. In the present study, effects of ATP were studied on axons and Schwann cells of C fibres in isolated rat vagus nerves. A combination of a computerised threshold tracking technique with photometric and confocal measurements of the free intracellular Ca2+ concentration revealed differences in the effect of ATP and related compounds. Pyridoxal-phosphate-6-azophenyl-2′,5′-disulphonic acid (iso-PPADS, an antagonist of ionotropic P2X receptors) completely blocked the excitatory effect of α,β-meATP on unmyelinated axons, whereas the effects of ATP and 2-Cl-ATP were only slightly changed. Moreover, the threshold lowering effects of ATP and 2-Cl-ATP, but not of α,β-meATP, were accompanied by intracellular Ca2+ transients. In confocal imaging experiments, the lectin IB4 was used to identify unmyelinated nerve fibres and their ensheathing Schwann cells. The Schwann cells were identified as the cellular elements underlying ATP-induced Ca2+ transients. In addition, an increase in axonal excitability of C fibres was seen during a rise in [Ca2+]i induced by inhibition of the endoplasmic Ca2+ ATPase with cyclopiazonic acid. These data show that an increase of the extracellular ATP concentration in an intact peripheral nerve trunk activates both axons and Schwann cells. It appears that P2 nucleotide receptors on Schwann cells may contribute to the excitatory effect of ATP observed on unmyelinated, including nociceptive, axons.

P2 nucleotide receptors in peripheral nerve trunk

AbstractThere is considerable interest in the possibility that ATP may function as a peripheral pain mediator. Most of the studies underlying this idea are electrophysiological recordings from sensory cell bodies, as nociceptive axons with diameters of 1 to 3 μm are not accessible by intracellular electrophysiological methods. However, the most important region for conduction of nociceptive information is thin axons in the peripheral nerve trunk. These nociceptive axons are in close contact with ensheathing Schwann cells, which also cannot easily be studied in situ by conventional recording techniques. In this review, we describe new methods that have been used to study the effects of ATP on unmyelinated axons and Schwann cells in intact peripheral nerve preparations. Threshold tracking of compound C fibre potentials and confocal calcium imaging revealed that extracellular ATP has rapid excitatory effects on both axons and Schwann cells in peripheral nerve trunk. Thereby, at least four different ionotropic and metabotropic P2 receptors were separated by pharmacological profiles. These receptors (P2X2/3 on unmyelinated axons; P2Y1, P2Y2, and P2X7 on Schwann cells) would allow for rapid interactions between axons and Schwann cells. It is suggested that purinergic signalling in peripheral nerve trunk contributes not only to pain transduction but might be involved in mechanosensitivity, inflammation, proliferation, and demyelination. Drug Dev. Res. 52:83–88, 2001. © 2001 Wiley‐Liss, Inc.

Sectional Neuroanatomy of the Upper Limb II: Shoulder and Upper Arm

This article is the second in a series of three that presents an anatomic functional guide to the peripheral innervation of the shoulder and upper limb. It illustrates the axial anatomy of the shoulder and upper arm. The next article continues this format for the lower arm and hand. Together, all three papers can be used to rapidly identify each upper limb muscle and its innervation(s). They can also be used to locate the peripheral nerve trunks, and correlate lesions with the classic pattern(s) of muscle denervation and altered sensation.

Approaches permitting and enhancing motoneuron regeneration after spinal cord, ventral root, plexus and peripheral nerve injuries.

The motoneuron has a strong ability to regenerate after injury. However, the problems of nerve cell survival after a proximal axotomy, difficulty in axonal elongation after intraspinal lesion and the lack of target specificity during nerve fibre regrowth interfere with a good functional restitution. Current research has addressed these impediments. New approaches for the management of complicated as well as intraspinal lesions and peripheral nerve trunk injuries are described.

Crow-Fukase syndrome.

Crow-Fukase syndrome is a unique multisystem disorder that is also known as POEMS syndrome (an acronym for polyneuropathy, organomegaly, endocrinopathy, the presence of M-protein and skin change). This syndrome is strongly associated with plasma cell dyscrasia. Circulating light chains of M component, almost invariably IgG lambda or IgA lambda, are found in 75% of patients. Neuropathologically, segmental demyelination, particularly in the proximal segment of the peripheral nerve trunk, is the primary process. Axonal degeneration and marked endoneurial edema are also characteristic. Focal excessive myelin outfolds with globular features corresponding to periodicity and paranodal enlargement of myelin are also highly characteristic of this syndrome. Vascular endothelial growth factor (VEGF) was found to be specifically and highly elevated in the serum of patients with this syndrome, suggesting a pathogenic role. M-protein, interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha are also considered to be involved in the pathogenesis. Treatment consists of radiation and surgical resection of the myeloma, chemotherapy, and a high dose of intravenous immunoglobulin (IVIg).

Expression of glial cell line-derived neurotrophic factor family of growth factors in peripheral nerve injury in rats.

The glial cell line-derived neurotrophic factor (GDNF) family of growth factors may be involved in the regenerative support of neurons in the peripheral nervous system. In order to study the role of these growth factors and their receptors following rat peripheral nerve injury we examined the changes in their mRNA levels in the spinal cord, the dorsal root ganglia and the peripheral nerve trunk. Following transaction of the sciatic nerve GDNF mRNA was up-regulated rapidly in the denervated nerve distal to the cut along with the mRNA for one of its receptors, GFRalpha-1. GFRalpha-1 mRNA was also increased in the DRG ipsilateral to the nerve injury suggesting that GDNF may be involved in the trophic support of DRG sensory neurons. In contrast there were no analogous changes in the mRNA levels of neurturin, persephin and artemin following injury.