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Update on peripheral nerve injuries.

Experimental work relating to factors affecting nerve regeneration is reviewed. There is increasing evidence that the nerve sprouts are preprogrammed for their peripheral reinnervation; old endoneurial tubes being discarded. Fascicular suture shows no significant improvement in function compared with epineural suture. The importance for sensory re-education and the need for repeatable sensory function tests is emphasized. Recent experimental work on the mechanisms of causalgia is reviewed and management of painful peripheral nerve disorders discussed. Striking advances have been made in the diagnosis, surgical treatment and rehabilitation of traction lesions of the brachial plexus. These are discussed with special reference to electrodiagnosis, functional splinting and management of pain. Surgery for obstetric palsies is now being undertaken and similar lesions to those in the adult being repaired with success. Reconstructive procedures for permanent paralysis are reviewed. Postirradiation plexus lesions present a formidable challenge but surgery can sometimes alleviate pain.

Brachial Plexus↗

Determination of the intracellular Ca2+ concentration in the N1E-115 neuronal cell line in perspective of its use for peripheric nerve regeneration.

Entubulation repair of peripheral nerve injuries has a lengthy history. Several experimental and clinical studies have explored the effectiveness of many biodegradable and non-degradable tubes with or without addition of molecules and cells. The main objective of the present study was to develop an economical and also an easy way for culturing a neural cell line which was capable of growing, differentiating and producing locally nerve growth factors that are otherwise extremely expensive, inside 90 PLA/10 PLG nerve guides. For this purpose the authors have chosen the N1E-115 cell line, a clone of cells derived from mouse neuroblastoma C-1300 with the perspective of using this differentiated cellular system to cover the inside of 90 PLA/10 PLG nerve guides placed to bridge a gap in the rat sciatic nerve experimental model. The N1E-115 cells proliferate in normal culture medium but undergo neuronal differentiation in response to DMSO. Upon induction of differentiation, proliferation of N1E-115 cells ceases, extensive neurite outgrowth is observed and the membranes become highly excitable. While it is known that Ca2+ serves as an important intracellular signal for various cellular processes, such as growth and differentiation. It is also known that can be toxic to cells and is involved in the triggering of events leading to excitotoxic cell death in neurons. The [Ca2+]i in non-differentiated N1E-115 cells and after distinct periods of differentiation, have been determined by the epifluorescence technique using the Fura-2-AM probe. The results of this quantitative assessment revealed that N1E-115 cells which undergo neuronal differentiation for 48 hours in the presence of 1.5% DMSO are best qualified to be used to cover the interior of the nerve guides since the [Ca2+]i was not found to be elevated indicating thus that the onset the cell death processes was not occurred.

Animals↗

Chronic inflammatory demyelinating polyneuropathy in childhood: ultrastructural features of peripheral nerve biopsies in four cases.

Peripheral nerve biopsies (PNB) from four children suffering from subacute or chronic inflammatory demyelinating polyneuropathy were studied by electron microscopy. Remyelinating features with onion bulb formations, inflammatory cell infiltrates and active demyelinating lesions were strongly suggestive of the disease. In the first case, a second PNB, performed after 7 months of severe subacute course, showed a striking evolution of the lesions. In the second case and in spite of severe neurological symptoms, the PNB was almost normal, suggesting that inflammatory lesions were mainly located in the proximal parts of the nerve. No signs of active demyelination could be seen in the third case but onion bulb formations and inflammatory cell infiltrates were present. In the fourth case, characteristic lesions of active demyelination were associated with a history of familial polyneuropathy; this association suggests an auto-immune process in certain kindreds with hereditary motor and sensory neuropathy.

Adolescent↗

Expression of Thy-1 antigen in reactive endoneurial capillaries of the rat following peripheral nerve damage.

Immunohistochemical staining of Thy-1 antigen was studied in rat peripheral nerves shortly after a complete crush lesion and after an epineural depot injection of lysophosphatidylcholine-palmitate (lysoPC). The Thy-1 antigen was expressed in endoneurial capillaries after 20-30 h and was visible previous to alterations in the axolemma or other signs of neural damage with the exception of endoneurial oedema formation. Thy-1 positive capillaries were restricted to the vicinity of degenerating nerve fibres in partially damaged nerves following epineural depot injection of lysoPC. It is therefore concluded that expression of the Thy-1 antigen in response to peripheral nerve damage in reactive endoneurial capillaries is an active process and not due to diffusion from degenerating axolemmata. Thy-1 staining could be used as a marker of reactive endoneurial capillaries in pathological conditions of peripheral nerves.

Animals↗

Neuromodulation: spinal cord and peripheral nerve stimulation.

Spinal cord and peripheral nerve stimulation for relief of chronic intractable pain have been used since the mid-1960s. Multiple mechanisms of action have been theorized without a clear-cut winner. The early frustrations with patient selection criteria and equipment difficulties have diminished secondary to carefully controlled studies and improvements in equipment designs. Efficacy studies consistently show an overall 50% improvement in long-term pain control in patients who have failed conservative or other invasive modalities. With improvements in today's technology, one hopes that better analgesia will be attainable.

Electric Stimulation Therapy↗

Multimodal frequency distribution analysis of peripheral nerves.

In morphometric studies of peripheral nerves, the statistical analysis of such data as axon diameters is complicated by the presence of multimodal distributions. Nerve fiber diameters, for example, cannot be analyzed by classical parametric tests, and such descriptive statistics as mean or variance lose much of their usefulness. The recent development of stochastic catastrophe models offers a new parametric tool with which to describe multimodal distributions. This paper describes our development of a PASCAL computer program that permitted the modelling, comparison and segmentation of multimodal distributions. The method is based on a description of the multimodal frequency distributions by probability density functions of the canonical exponential family.

Axons↗

Rehabilitation of peripheral nerve injuries.

Traumatic injuries to peripheral nerves pose complex challenges to both military and civilian physicians. Treatment of nerve injuries must consider all aspects of the inherent disability. Pain control is of paramount importance. Little will be accomplished until pain is brought down to tolerable levels. Rehabilitation needs to be instituted as first-line treatment. Focus must be first placed on protection of the affected area from complications stemming from disuse and immobility and then on enhancement of strength, flexibility, sensory discrimination, and dexterity. Early intervention sets the stage for optimal physiologic and functional recovery.

Anti-Inflammatory Agents, Non-Steroidal↗

Vascularized allogeneic joint, muscle, and peripheral nerve transplantation.

Joint, muscle, and peripheral nerve allotransplantation was done with short-term cyclosporine immunosuppression. To investigate the effectiveness of this regimen, the allografts were examined after withdrawal of cyclosporine. Using inbred rats, vascularized orthotopic allotransplantation of the knee joint, rectus femoris muscle, and great saphenous nerve was done across a major histocompatibility complex barrier. Cyclosporine was administered for 4 to 6 weeks postoperatively, and the grafts were observed until Week 12. Long-term administration of cyclosporine and nonvascularized transplantation were used as controls. Although rejection of the allografts could be delayed for 2 to 3 weeks after the withdrawal of cyclosporine, all transplanted joints, muscles, and nerves eventually were rejected completely and immunotolerance could not be induced. The joint allografts at first achieved bony union, but eventually were destroyed because of pathologic fractures. In the group treated with long-term immunosuppression, the allografts showed no rejection and functional improvement was obtained. However, rats given a high dose (10 mg/kg per day) of cyclosporine died from adverse effects of the drug by Week 12. In the nonvascularized treatment group, the results were poor in every patient, and the need for graft vascularization for skeletal tissue allotransplantation was confirmed.

Animals↗

Loss of GABA-immunoreactivity in the spinal dorsal horn of rats with peripheral nerve injury and promotion of recovery by adrenal medullary grafts.

Abnormal pain-related behaviour that accompanies peripheral nerve injury may be the result of altered spinal neuronal function. The long-term loss of inhibitory function by GABA neurons in particular may be a mechanism by which abnormal neural hyperactivity occurs, leading to exaggerated sensory processing following nerve injury. In order to assess this, changes in spinal GABA immunoreactivity at several time points following constriction nerve injury were quantified in parallel with behavioural assessments of abnormal sensory responses to noxious and innocuous stimuli. In addition, the effects of spinal adrenal medullary transplants were determined since previous findings have demonstrated alleviation of behavioural pain symptoms by such transplants. In response to unilateral sciatic nerve injury, GABAergic profiles normally found in lumbar dorsal horn laminae I-III significantly decreased. The decrease was apparent three days following ligation, particularly on the side ipsilateral to the nerve injury. By two weeks, no GABAergic profiles could be seen, with the deficit appearing in the spinal dorsal horn both ipsilateral and contralateral to the unilateral peripheral nerve injury. Marked decreases in GABA-immunoreactive profiles persisted for at least up to five weeks post-injury, with partial restoration occurring by seven weeks. However, even at seven weeks, losses in GABA-immunoreactive profiles persisted in the dorsal horn ipsilateral to peripheral nerve injury. These findings were comparable in animals receiving control striated muscle transplants. In contrast, adrenal medullary transplants markedly reduced the loss in GABA-immunoreactive profiles at all time-points examined. In addition, GABA-immunoreactive profile levels were normalized near that of intact animals by five to seven weeks following nerve injury in animals with adrenal medullary transplants. Parallel improvements in sensory responses to innocuous and noxious stimuli were also observed in these animals. The results of this study indicate that peripheral nerve injury can result in severe losses in spinal inhibitory mechanisms, possibly leading to exaggerated sensory processes in persistent pain states. In addition, adrenal medullary transplants may provide a neuroprotective function in promoting recovery and improving long-term survival of GABAergic neurons in the spinal dorsal horn which have been damaged by excitotoxic injury.

Adrenal Medulla↗

Comparative studies on myelin proteins in mammalian peripheral nerve.

Myelin proteins in mammalian peripheral nerve were studied comparatively. 1. While each content of P1 and P2 in the myelin varied among species, additional content of P1 and P2 are relatively constant. 2. The antigenic determinants of P2 for induction of experimental allergic neuritis were reported. 3. Amino acid sequence analysis of P0 revealed that P0 is conserved across species and belongs to the immunoglobulin superfamily. 4. The characteristic carbohydrate chain of P0 containing sulfate and sialic acid showed a positive reaction to the molecule-related immunity and adhesion. 5. Molecular architecture of the myelin is discussed.

Amino Acid Sequence↗

Electrophysiologic evaluation of peripheral nerve regeneration through allografts immunosuppressed with cyclosporin.

A model was designed to evaluate the long-term in vivo electrophysiology of rat peripheral nerve transplants. The application of this model was demonstrated using cyclosporin (CSA) immunosuppression of recipient animals to facilitate peripheral nerve regeneration through nerve allografts. Isogenic Brown Norway (BN) rats [RT1n] were divided into three groups: two received Lewis (LE) rat [RT1l] allografts and one received BN isografts. One allograft recipient group received CSA immunosuppression for the duration of the investigation (150 days). Successful nerve regeneration in the isograft and the immunosuppressed allograft recipient groups was determined by immunohistochemical methods and serial in vivo electrophysiologic techniques to measure nerve conduction velocity and evoked compound muscle action potential amplitude. Statistical analysis of these results indicate that: (a) CSA immunosuppression of peripheral nerve allograft recipients facilitates peripheral nerve regeneration which is indistinguishable from isograft recipient controls at the functioning axon level; and (b) in vivo electrophysiologic monitoring in this model is particularly useful for long term peripheral nerve transplantation studies permitting serial assessment of regeneration with little morbidity.

Action Potentials↗

[A preliminary study on the morphological changes of the microvasculature following the peripheral nerve autografting].

The microvasculature of peripheral nerve following autografting was studied by scanning electron microscopy. The newly-formed capillaries was also examined by transmission electron microscopy. Capillaries of a fascicle were divided into an extrafascicular vascular plexus and an intrafascicular capillary bed; the former capillaries formed networks, while the latter capillaries ran longitudinally and formed slightly spiral curve. Normal intrafascicular capillaries had tight junctions, a continuous basement membrane and pericytes. On the suture line, capillaries of the graft and those of the host were connected by newly developed sinusoidal capillaries, which were formed at the extrafacicular region earlier than at the intrafascicular region. Newly developed sinusoidal capillaries were transformed into glomerulus-like capillaries and formed fine networks. These networks exhibited a normal capillary architecture after reconstruction. The endothelium of newly-formed capillaries showed a discontinuous basement membrane at the early stage of regeneration. An intrafascicular capillary bed was present in the middle part of the graft.

Animals↗

[Results of surgical treatment for traumatic injury of upper extremity peripheral nerves taken from personal material].

A series of 52 patients with peripheral nerve injury, treated operatively is presented. Motor function has been assessed according to Highet (MO-M5). Sensory function has been evaluated according to Nicholson and Seddon (S0-S4). An attempt to show decisive factors for successful peripheral nerve reconstruction. Clinical analysis proved surgical technique, modified with experience gained influences the final result remarkably. Imposition of microsurgical techniques and instrumentation as well as operative microscopy improved efficacy of the treatment. Delay of final reconstruction worsens ultimate outcome. Age of the patient and coexisting injury of the skin, tendons and bone that change conditions of nerve regeneration are also important. The longer the skin nerve graft is the worse motor and sensory recovery.

Adolescent↗

High-resolution sonography of lower extremity peripheral nerves: anatomic correlation and spectrum of disease.

OBJECTIVE: The value of sonography for the diagnosis of diseases of the peripheral nervous system is only little known. This image presentation is intended to raise the awareness of sonographers and clinicians of the potential of sonography by giving an anatomic-sonographic correlation of lower extremity peripheral nerves and an overview of commonly encountered diseases. METHODS: On 2 lower extremity cadaver specimens, peripheral nerves were imaged in typical locations such as the tarsal tunnel. During sonography the nerve was injected with blue dye, and thin-slice anatomic sections were obtained at the scan level with a chain saw. In addition, sonographic images of patients with typical diseases are shown. RESULTS: An excellent anatomic-sonographic correlation was obtained, which underlines the feasibility of sonography for imaging of lower extremity peripheral nerves. Reliable results may be obtained with sonography of typical disease processes of lower extremity peripheral nerves. CONCLUSIONS: Recent developments in sonographic technology such as the introduction of high-frequency linear array transducers, compound imaging, and extended field-of-view imaging strongly improve the applicability of transcutaneous sonography for the examination of peripheral nerve disease.

Cadaver↗

Evidence for nitric oxide and nitric oxide synthase activity in proximal stumps of transected peripheral nerves.

Nitric oxide may be liberated as an inflammatory mediator within injured peripheral nerve trunks. We evaluated the proximal stumps of injured peripheral nerve stumps that later form neuromas or regenerative nerve sprouts, for evidence of local nitric oxide elaboration and activity. Proximal stumps were created in male Sprague-Dawley rats by sectioning of the sciatic nerve and resection of its distal portions and branches. There was striking physiological evidence of nitric oxide activity at the tips of 48-h and 14-day-old proximal nerve stumps. We detected local nitric oxide-mediated hyperemia of both extrinsic plexus and endoneurial microvessels that was reversible, in a dose-dependent stereospecific fashion, by the broad-spectrum nitric oxide synthase inhibitors, Nomega-nitro-L-arginine-methyl ester or Nomega-nitro-L-arginine, but not by 7-nitroindazole, an inhibitor with relative selectivity for neuronal nitric oxide. Immunohistochemical studies provided evidence for the localization of nitric oxide generators at the same sites. In 48-h but not 14-day stumps increased expression of two isoforms of nitric oxide synthase was detected: endothelial nitric oxide and to a much lesser extent neuronal nitric oxide synthase. Both isoforms appeared in axonal endbulb-like profiles that co-localized with neurofilament immunostaining. Western immunoblots identified a band consistent with endothelial nitric oxide synthase expression. In 14-day stumps with early neuroma formation, but not 48-h stumps, there was staining for immunological nitric oxide synthase in some endoneurial and epineurial macrophages. Total nitric oxide synthase biochemical enzymatic activity, measured by labelled arginine to citrulline conversion, was increased in 14-day but not 48-h stumps. Injured peripheral nerves have evidence of early nitric oxide action, nitric oxide synthase expression and nitric oxide activity in proximal nerve stumps. Nitric oxide may have an important impact on the regenerative milieu.

Animals↗

[The Dellon tube in injuries of peripheral nerves].

Experimental efforts are being undertaken to improve nerve transplantation as a method for peripheral nerve repair. Major disadvantages of nerve transplantation are the creation of neurologic deficits at the donor site and the limited availability of nerve grafts. Mackinnon and Dellon propose the interposition of synthetic, biodegradable tubes as a nerve conduit for clinical use. This method is described according to its theoretical background and the surgical technique. The interposition of synthetic tubes seems possible for short defects in finger nerves, but will render unfavourable results in long defects of peripheral mixed nerves.

Animals↗

Clinical correlation with anti-peripheral-nerve myelin antibodies in Guillain-Barré syndrome.

Anti-peripheral-nerve myelin antibodies (anti-PNM Ab) can be detected in the serum of all patients with acute-phase Guillain-Barré syndrome (GBS) thus far tested. Correlation of the titer of this antibody with the clinical course would help to establish a role for the humoral immune system in the pathophysiology of GBS. In this study, anti-PNM Ab levels were measured in serial serum samples of 7 patients with GBS with an assay that detects antibodies bound to peripheral nerve myelin antigens by fixation of the first component of complement. Although the titers of anti-PNM Ab detected in these patients varied between 0 and 256 U/ml, the antibody titer was always highest on admission (35 to 256 U/ml) and rapidly declined during a one-to-three-week period. Disappearance of antibodies or very low levels of them correlated with cessation of progression and considerable clinical improvement as documented by increased pulmonary vital capacity and muscular strength. Low but measurable antibody titers (5 to 12 U/ml) were frequently found up to four months following the acute neurological deficit. The close temporal relationship between anti-PNM Ab titer and the clinical course in GBS suggests that antibody most likely participates through complement activation in peripheral nerve demyelination.

Adolescent↗

Further development of reconstructive and cell tissue-engineering technology for treatment of complete peripheral nerve injury in rats.

UNLABELLED: In this work we evaluated the efficacy of biodegradable composite co-polymer guiding neurotube, based on tissue-engineering technology, for the treatment of complete peripheral nerve injury where the nerve defect is significant. The right sciatic nerve of 12 three-month-old rats was completely transected and peripheral nerve segment was removed. A 2.2-cm biodegradable co-polymer neurotube containing viscous gel (NVR-N-Gel) with survival factors, neuroprotective agents and Schwann cells was placed between the proximal and the distal parts of the transected nerve for reconnection a 2-cm nerve defect. The proximal and distal parts of the nerve were fixed into the neurotube using 10-0 sutures. Ultrasound observation showed growth of the axons into the composite neurotube 2 months after the surgery. Electrophysiological study indicated compound muscle action potentials in nine out of 12 rats, 2-4 months after peripheral nerve reconstructive surgery. The postoperative follow-up (up to 4 months) on the operated rats that underwent peripheral nerve reconstruction using composite co-polymer neurotube, showed beginning of re-establishment of active foot movements. The tube was dissolved and nerve showed complete reconnection. Histological observation of the nerve showed growth of myelinated axons into the site where a 2-cm nerve defect replaced by composite co-polymer neurotube and into the distal part of the nerve. IN CONCLUSION: (1) an innovative composite neurotube for reconstruction of significant loss of peripheral nerve segment is described; (2) a viscous gel, containing survival factors, neuroprotective agents and Schwann cells served as a regenerative environment for repair. Further investigations of this reconstructive procedure are being conducted.

Animals↗