Staged Phrenic Nerve Elongation and Free Functional Gracilis Muscle Transplantation-A Possible Option for Late Reconstruction in Chronic Brachial Plexus Injury.

PURPOSE: In patients with late brachial plexus birth injuries, sequelae after acute flaccid myelitis, or chronic adult brachial plexus injury, donor nerves for functioning muscle transplantation are often scarce. We present the results of a potential strategy using the phrenic nerve with staged free gracilis transplantation for upper extremity reanimation in these scenarios. METHODS: A retrospective review was performed on an institutional database of brachial plexus injury or patients with palsy. All patients underwent a staged reconstruction in which the ipsilateral phrenic nerve was extended by an autogenous nerve graft (PhNG), followed by free-functioning gracilis transplantation (PhNG-gracilis). RESULTS: Nine patients (6 cases of late brachial plexus birth injuries, 2 of acute flaccid myelitis, and 1 of adult chronic brachial plexus injury) were included in this study. The median follow-up period following the PhNG-gracilis procedure was 27 months (range, 12-72 months). The goals of the staged PhNG and PhNG-gracilis were primarily finger extension or finger flexion. In some patients, the technique was used to improve both elbow and finger function, tunneling the muscle through the flexor compartment of the upper arm and under the mobile wad at the elbow. All patients exhibited improvement of muscle strength, including in finger extension (4 patients) from M0 to M2; finger flexion (3 patients) from M0 to M3; elbow extension (1 patient) from M0 to M2; and elbow flexion (1 patient) from M2 to M4. CONCLUSIONS: A 2-stage PhNG-gracilis may restore or enhance the residual elbow and/or finger paralysis in chronic brachial plexus injuries. A minimum follow-up period of 3 years is recommended. This technique may remain useful as one of the last reconstructive options to increase power in patients with scarce donor nerves. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

A comparative assessment of lengthening followed by end-to-end repair and isograft repair of chronically injured peripheral nerves.

In order to repair chronic nerve injuries (injuries repaired after a long delay), the damaged nerve segments are resected and stumps are bridged by grafts. Autografts remain the gold-standard, but outcomes are typically poor, even after long periods of recovery. In a recent study, we described the use of a nerve lengthening device to gradually elongate the proximal stump of a transected nerve towards the distal stump, enabling a tension-free end-to-end repair. This approach showed significantly improved outcomes in comparison to autografts in repairing acutely injured nerves. In this study, we compared the use of nerve lengthening/end-to-end repair (LETER) to isograft repair of chronically transected nerves in a rat model. Structural and functional regenerative outcomes following LETER were comparable to isograft-based repair, with no significant differences found in outcomes involving functional recovery or axon growth. These data demonstrate the feasibility of nerve lengthening as a viable graft-free strategy for repairing chronically injured nerves. Not unexpectedly, outcomes for chronic nerve injuries were less favorable in both groups compared to repair of acutely injured nerves. Nonetheless, the findings provide insight into barriers to restoring function after chronic nerve injury through novel comprehensive characterization of a diverse set of neuromuscular outcomes. This analysis revealed key parameters predicting functional recovery.

Nerve lengthening and subsequent end-to-end repair yield more favourable outcomes compared with autograft repair of rat sciatic nerve defects.

Outcomes of end-to-end nerve repairs are more successful compared with outcomes of repairs bridged by nerve grafts. However, end-to-end repairs are not always possible for large nerve gaps, as excessive tension may cause catastrophic failure. In this study, we built on previous nerve-lengthening studies to test the hypotheses that gradual lengthening of the proximal stump across a large nerve gap enables an end-to-end repair and such a repair results in more favourable regenerative outcomes than autografts, which represent the gold standard in bridging nerve gaps. To test these, we compared structural and functional outcomes in Lewis rats after repair of sciatic nerve gaps using either autografts or a novel compact internal fixator device, which was used to lengthen proximal nerve stumps towards the distal stump over 2 weeks, prior to end-to-end repair. Twelve weeks after the initial injury, outcomes following nerve lengthening/end-to-end repair were either comparable or superior in every measure compared with repair by autografting. The sciatic functional index was not significantly different between groups at 12 weeks. However, we observed a reduced rate of contracture and corresponding significant increase in paw length in the lengthening group. This functional improvement was consistent with structural regeneration; axonal growth distal to the injury was denser and more evenly distributed compared with the autograft group, suggesting substantial regeneration into both tibial and peroneal branches of the sciatic nerve. Our findings show that end-to-end repairs following nerve lengthening are possible for large gaps and that this strategy may be superior to graft-based repairs.

[Experimental study of the effect of the sciatic nerve elongation on pain in rats].

OBJECTIVE: To investigate the effect of the sciatic nerve elongation on pain in rats. METHODS: Thirty-six adult male Wistar rats of SPF grade, weighing 250-300 g. Eighteen of them were randomly divided into 3 groups, 6 rats in each group. They were sciatic nerve elongation group (group A), nerve no-elongation group (group B), and nerve ligation group (group C). The model of 10-mm sciatic nerve defect was established in all 3 groups. The sciatic nerve was extended at a speed of 1 mm/d for 14 days in group A. The group B was only installed with external fixation. The nerve stumps were ligated in the group C. At 3, 7, 10, and 14 days after operation, the foot injury was evaluated by the autotomy scoring scale. At 14 days after operation, the dorsal root ganglia (DRG) of L 4-S 1 spinal cord of rats in each group was observed by tumor necrosis factor α (TNF-α) immunohistochemical staining, and the primary antibodies were replaced by pure serum as negative control group. Another 18 rats were randomly divided into 3 groups, 6 rats in each group. They were sciatic nerve elongation group (group A1), nerve no-elongation group (group B1), positive control group (group C1). In groups A1 and B1, the 10-mm long sciatic nerve defect model was established by the same method as groups A and B, and then fixed with external fixation. Nerve elongation was done or not done without anesthesia at 3 days after operation. In group C1, no modeling was done and 20 µL 2.5% formaldehyde was injected into the toes. After 90 minutes, the dorsal horn of spinal cord of L 4-S 1 segment of rats was cutting for c-Fos immunohistochemical staining and the number of positive cells was counted. Primary antibodies were replaced with pure serum as negative control group. RESULTS: The autotomy scores of rats in groups B and C gradually increased postoperatively, and group A remained stable at 0.25±0.50. The scores of group C were significantly higher than those of group A and group B at each time point postoperatively ( P<0.05). The scores of group A were significantly lower than those of group B at 10 and 14 days postoperatively ( P<0.05). TNF-α immunohistochemical staining showed that the TNF-α expression in group A was weak, slightly positive (+/-); in group B was positive (+); in group C was strongly positive (++); and the negative control group had no TNF-α expression (-). c-Fos immunohistochemical staining showed that the c-Fos expressions in groups A1 and B1 were weak positive, in group C1 was strong positive, and negative control group had no c-Fos positive expression. The number of c-Fos positive cells in groups A1, B1, C1, and negative control group were (21.5±6.6), (19.3±8.1), (95.6±7.4), and 0 cells/field, respectively, and group C1 was significantly higher than groups A1 and B1 ( P<0.05), there was no significant difference between group A1 and group B1 ( P>0.05). CONCLUSION: Nerve elongation does not cause obvious pain neither during the operation of elongation nor throughout the whole elongation.

Nerve stretching: a history of tension.

Stretch injuries are among the most devastating forms of peripheral nerve injury; unfortunately, the scientific understanding of nerve biomechanics is widely and impressively conflicting. Experimental models are unique and disparate, victim to different testing conditions, and thus yield gulfs between conclusions. The details of the divergent reports on nerve biomechanics are essential for critical appraisal as we try to understand clinical stretch injuries in light of research evidence. These conflicts preclude broad conclusion, but they highlight a duality in thought on nerve stretch and, within the details, some agreement exists. To synthesize trends in nerve stretch understanding, the author describes the literature since its introduction in the 19th century. Research has paralleled clinical inquiry, so nerve research can be divided into epochs based largely on clinical or scientific technique. The first epoch revolves around therapeutic nerve stretching-a procedure known as neurectasy-in the late 19th century. The second epoch involves studies of nerves repaired under tension in the early 20th century, often the result of war. The third epoch occurs later in the 20th century and is notable for increasing scientific refinement and disagreement. A fourth epoch of research from the 21st century is just dawning. More than 150 years of research has demonstrated a stable and inherent duality: the terribly destructive impact of stretch injuries, as well as the therapeutic benefits from nerve stretching. Yet, despite significant study, the precise border between safe and damaging stretch remains an enigma.

[Stretch-induced axon growth: a universal, yet poorly explored process]. / La croissance axonale par étirement : un processus universel encore peu exploré.

The growth of axons is a key step in neuronal circuit assembly. The axon starts elongating with the migration of its growth cone in response to molecular signals present in the surrounding embryonic tissues. Following the formation of a synapse between the axon and the target cell, the distance which separates the cell body from the synapse continues to increase to accommodate the growth of the organism. This second phase of elongation, which is universal and crucial since it contributes to an important proportion of the final axon size, has been historically referred to as "stretch-induced axon growth". It is indeed likely to result from a mechanical tension generated by the growth of the body, but the underlying mechanisms remain poorly characterized. This article reviews the experimental studies of this process, mainly analysed on cultured neurons so far. The recent development of in vivo imaging techniques and tools to probe and perturb mechanical forces within embryos will shed new light on this universal mode of axonal growth. This knowledge may inspire the design of novel tissue engineering strategies dedicated to brain and spinal cord repair.

Median nerve neuropathy

The median nerve is the most important nerve in the upper extremity, as it is responsible for most of the sensation of the hand, the fine motor functions of the thumb, and finger grasping. Median neuropathies most commonly occur as compressive neuropathy or entrapment neuropathy, but sometimes as neuritis without any compressive lesion. Carpal tunnel syndrome (CTS), anterior interosseous nerve syndrome, and pronator teres syndrome are the subtypes of median nerve neuropathies, of which CTS is the most common. Median neuropathies can be diagnosed clinically by careful history-taking and a physical examination. Typical symptoms of CTS include night pain (crying), a tingling sensation of the radial digits, numbness or paresthesia, clumsiness, and atrophy of the thenar muscles. Electrophysiologic testing can be used for confirmation of the diagnosis and for documentation before surgical treatment. Imaging modalities including ultrasonography or magnetic resonance imaging can be used to ensure diagnostic accuracy and to detect unusual causes of compression. Conservative treatments include rest, bracing, nerve stretching, non-steroidal anti-inflammatory drugs, and steroid injections. If nonsurgical approaches are unsatisfactory or the nerve damage is severe, surgical treatment should be considered. Carpal tunnel release for CTS is a relatively simple procedure that involves division of the transverse carpal ligament and decompression of the median nerve. Early diagnosis and proper management are important, as muscle atrophy and sensory loss may persist when surgical release is delayed in patients with advanced disease.

[New treatment for peripheral nerve defects: nerve elongation].

Peripheral nerve defects are still a major challenge in clinical practice, and the most commonly used method of treatment for peripheral nerve defects is nerve transplantation, which has certain limitations and shortcomings, so new repair methods and techniques are needed. The peripheral nerve is elongated in limb lengthening surgery without injury, from which we got inspirations and proposed a new method to repair peripheral nerve defects: peripheral nerve elongation. The peripheral nerve could beelongated by a certain percent, but the physiological change and the maximum elongation range were still unknown. This study discussed the endurance, the physiological and pathological change of peripheral nerve elongation in detail, and got a lot of useful data. First, we developed peripheral nerve extender which could match the slow and even extension of peripheral nerve. Then, our animal experiment result confirmed that the peripheral nerve had better endurance for chronic elongation than that of acute elongation and cleared the extensibility of peripheral nerve and the range of repair for peripheral nerve defects. Our result also revealed the histological basis and changed the rule for pathological physiology of peripheral nerve elongation: the most important structure foundation of peripheral nerve elongation was Fontana band, which was the coiling of nerve fibers under the epineurium, so peripheral nerve could be stretched for 8.5%-10.0% without injury because of the Fontana band. We confirmed that peripheral nerve extending technology could have the same repair effect as traditional nerve transplantation through animal experiments. Finally, we compared the clinical outcomes between nerve elongation and performance of the conventional method in the repair of short-distance transection injuries in human elbows, and the post-operative follow-up results demonstrated that early neurological function recovery was better in the nerve elongation group than in the conventional group. On the whole, all of these experimental results revealed the physiological phenomenon of peripheral nerve elongation, and described the physiological change and stretch range in detail. The systematic research results have filled the blank in this field, which is very helpful for clinical limb lengthening surgery, the design of elongation surgery and the evaluation of the peripheral nerve stretch injury. Peripheral nerve elongation will become an innovative treatment technology in repairing peripheral nerve defects.

Secondary nerve lengthening to obtain full knee extension in popliteal pterygium syndrome.

Microsurgical nerve lengthening was performed in two siblings presenting a popliteal pterigium syndrome with a knee flexion contracture of 80 degrees. After the first attempt for nerve lengthening and knee extension elsewhere, a repeated lengthening was required due to continuing tip-toe walking and recurrent knee contracture at the age of 3 years. An extensive external and internal interfascicular microsurgical neurolysis resulted in a lengthening of the nerves. A full length of leg procedure had to be performed, inclusive of Achilles tendon lengthening to obtain a complete extension of the knee and a 90-degree ankle flexion. Maintaining the leg in a fully extended position was obtained with a dynamic splinting in the first month after the operation. When timing the operation we have to consider the importance of adequate precision of the microsurgical neurolysis, down to the identification of the Fontana bands, and the adequate postoperative splinting.

Neuroma-in-continuity of the median nerve managed by nerve expansion and direct suture with vein conduit.

Autologous nerve grafting is the current standard for bridging large gaps in major sensory and motor nerves. It allows both function and pain improvement with predictable results. Clinical observations of nerve elongation caused by tumours have prompted experimental animal studies of induced gradual elongation of the nerve stump proximal to the gap. This technique allows direct suturing of the two nerve ends to bridge the gap. Here, we describe a case of neuroma-in-continuity of the median nerve managed by resection and direct suture after nerve elongation with a tissue expander. We are not aware of similar reported cases. Secondary repair 3 years after the initial injury improved the pain and hypersensitivity and restored a modest degree of protective sensory function (grade S1).

Simultaneous gradual lengthening of proximal and distal nerve stumps for repair of chronic peripheral nerve defect in rats.

We investigated nerve regeneration of rat sciatic nerves after chronic injury of 15 mm-defect by the gradual lengthening of proximal and distal nerve stumps. Thirty days after the primal injury, both stumps were grasped and lengthened at a rate of 1 mm per day using external nerve-lengthening devices for 15 days. Then end-to-end neurorrhaphy was performed. After the lengthening, both stumps were evaluated by immunohistochemical analysis. Nerve regeneration was evaluated by electrophysiological and histological studies at 12 weeks after the repair. In the lengthened proximal stump, Schwann cells and axons existed along the whole nerve stump. In the lengthened distal stump, Schwann cells exist along the overall length. The whole nerve trunk was lengthened. The nerve regeneration was comparable with the delayed end-to-end suture without nerve defect. We showed the feasibility of direct gradual lengthening of proximal and distal nerve stumps for the treatment of chronic segmental nerve defect.

New treatment for peripheral nerve defects: reconstruction of a 2 cm, monkey median nerve gap by direct lengthening of both nerve stumps.

We have developed a new treatment for peripheral nerve defects: nerve-lengthening method, and confirmed the efficacy and safety of our method using cynomolgus monkeys. A 20-mm defect in the median nerve of monkey's forearms was repaired through the simultaneous lengthening of both nerve stumps with original nerve-lengthening device. To evaluate nerve regeneration after neurorrhaphy, electrophysiological, histological, and functional recovery were examined and compared to the standard autografting. Nerve conduction velocity, axon maturation, and the result of functional test were superior in the nerve-lengthening method than in the autografting. And there were no adverse events associated with our method. We concluded that this method is practical for clinical application.

Effect of hyperbaric oxygen therapy on tense repair of the peripheral nerves.

BACKGROUND: After a peripheral nerve cut, tense repair of a nerve compromises circulation of the nerve at the injury site, making the site hypoxic. Hyperbaric oxygen might increase tissue oxygenation and therefore diminish the effects of injury. We investigated whether hyperbaric oxygen treatment affects peripheral nerve healing when repaired nerves are under tension. METHODS: Sixteen young female albino Wistar rats were used. Sciatic nerves of the animals were cut and a 3mm part of each nerve was excised. The animals were distributed into two groups: 1) The HBO2 group (n = 8), which received surgical repair and HBO2 therapy; and 2) The Control group (n = 8), which received only surgical repair. Walking track analysis was performed five times, on Days 12, 15, 18, 20 and 22 after surgery. The healing of sciatic nerves was evaluated by histopathological study and electrophysiological study. Pillai's Trace test and Mann-Whitney U-test were used for statistical analysis. RESULTS: Walking track analysis: Sciatic function index (SFI) scores of HBO2 group were significantly higher than SFI scores of Control group (p:0.026). Electrophysiological study: A statistical difference was not found between groups. Histopathological study: Counts of HBO2 group axons were significantly greater than in the control group (p: 0.008). CONCLUSIONS: In clinical practice, tension after nerve repair frequently occurs. However, neither grafting nor other current surgical methods are functionally perfect. Since primary end-to-end repair is known to be the best repair when possible, we think HBO2 allows for the use of primary repair even when nerve tension is foreseen.

The role of stretching in slow axonal transport.

Axonal stretching is linked to rapid rates of axonal elongation. Yet the impact of stretching on elongation and slow axonal transport is unclear. Here, we develop a mathematical model of slow axonal transport that incorporates the rate of axonal elongation, protein half-life, protein density, adhesion strength, and axonal viscosity to quantify the effects of axonal stretching. We find that under conditions where the axon (or nerve) is free of a substrate and lengthens at rapid rates (>4 mm day⁻¹), stretching can account for almost 50% of total anterograde axonal transport. These results suggest that it is possible to accelerate elongation and transport simultaneously by increasing either the axon's susceptibility to stretching or the forces that induce stretching. To our knowledge, this work is the first to incorporate the effects of stretching in a model of slow axonal transport. It has relevance to our understanding of neurite outgrowth during development and peripheral nerve regeneration after trauma, and hence to the development of treatments for spinal cord injury.

Functional and mechanical evaluation of nerve stretch injury.

Peripheral nerves undergo tensile loading in common physiological conditions, but stretch can also induce nerve pathology, impairing electrophysiological conduction. The level of strain nerves can tolerate and the functional deficits which result from exceeding this threshold are not thoroughly understood. To examine these phenomena, a novel system for tensile electrophysiology was created using a grease gap-recording chamber paired with a computerized micromanipulator and load cell. Guinea pig sciatic nerves were stretched beyond their maximum physiologic length to examine the effects of tension on signal conduction. Mechanical and electrophysiological data such as load, position, compound action potential amplitude, and signal latency were recorded in real-time. While 5% strain did not affect conduction, further elongation decreased amplitude approximately linearly with strain. These experiments verify the findings of prior studies into nerve stretch, and demonstrate the utility of this apparatus for investigating the mechanical and electrophysiological properties of nerves undergoing strain.

Resolution of Isolated Unilateral Hypoglossal Nerve Palsy Following Microvascular Decompression of the Intracranial Vertebral Artery

Isolated hypoglossal nerve paresis due to mechanical compression from a vascular lesion is very rare. We present a case of a 32-year-old man who presented with spontaneous abrupt-onset dysarthria, swallowing difficulty and left-sided tongue atrophy. Brain computed tomographic angiography and magnetic resonance imaging of the brainstem demonstrated an abnormal course of the left vertebral artery compressing the medulla oblongata at the exit zone of the hypoglossal rootlets that was relieved by microvascular decompression of the offending intracranial vertebral artery. This case supports the hypothesis that hypoglossal nerve palsy can be due to nerve stretching and compression by a pulsating normal vertebral artery. Microvascular decompression of the intracranial nerve and careful evaluation of the imaging studies can resolve unexpected isolated hypoglossal nerve palsy.

The current role of tissue engineering in head and neck reconstruction.

Tissue engineering is an emerging field that has the potential to revolutionize the field of reconstructive surgery by providing off-the-shelf replacement products. The literature has become replete with tissue engineering studies, and the aim of this article is to review the contemporary application of tissue-engineered products. The use of tissue-engineered cartilage, bone and nerve in head and neck reconstruction is discussed.

Prefabricated nerve conduits advance histomorphological and functional outcomes in nerve regeneration of the sciatic nerve of the rat.

Bridging a nerve defect is sometimes necessary to achieve nerve regeneration after injury. Different methods and conduit designs have been considered, but only isograft transplants or prefabricated conduits are available. This study presents a comparison of prefabricated conduits and isograft transplants in rats, with the aim of making suggestions for clinical settings. In rats of inbred strains LEW and DA, a 1.5cm defect of the sciatic nerve was reconstructed by isograft (n=10) or conduit (n=10). Untreated rats (n=10), sham-operated rats (n=10) and nerves of the non-operated contralateral limb served as controls. Regeneration was evaluated by histomorphological examination and with walking track analysis of the ankle stance angle (ASA) and the sciatic functional index (SFI). After 16 weeks, myelinization and ASA in the conduit group were significantly superior to that in the isograft group. There was no significant difference in SFI between the groups. Reconstruction in the isograft group showed a negative impact on the non-operated side. Conduits and isografts did not reach the morphological or functional levels of untreated or sham-operated animals. The results suggest preferential conduits should be used for nerve reconstruction.

Histological analysis of single peripheral nerve fiber in acute nerve elongation process.

To observe the histological alterations of single nerve fiber structures after nerve elongation by employing a rabbit peroneal nerve stretching model. 14 rabbits weighing mean 3. 0 kg (2.02-3.31 kg.) were used in the experiment. Two rabbits were used as control when only a sham operation was done (group one, 0% stretch). Acute stretching of the peroneal nerves to elongate them by 10% was done in 6 rabbits (group two, 10% elongation) and by 20% (group three, 20% elongation) in another 6 rabbits. All animals were evaluated by tissue staining technology in a teased-fiber study. The internodal lengths were measured, and nodes of Ranvier and Schmidt-Lanterman notch were observed. The nerve fiber length was increased after stretching. The mean internodal length was 1208.31 microm in group one, 1347.26 microm in group two, and 1411.35 microm in group three. Compared with the control group, mean internodal length was elongated by 11.50% in group two and 16.80% in group three. The difference was statistically significant. The node of Ranvier and Schmidt-Lanterman notch was wider in both group two and group three. Rupture of nerve fiber at the node of Ranvier was observed in group three. The peroneal nerve in rabbits can adapt to mild stretching by internodal length elongation. Elongation by 20% will cause structural rupture and therefore is the limit for nerve elongation.