Acetylglutamine facilitates motor recovery and alleviates neuropathic pain after brachial plexus root avulsion in rats.

BACKGROUND: Brachial plexus root avulsion (BPRA), a disabling peripheral nerve injury, induces substantial motoneuron death, motor axon degeneration and denervation of biceps muscles, leading to the loss of upper limb motor function. Acetylglutamine (N-acetyl-L-glutamine, NAG) has been proven to exert neuroprotective and anti-inflammatory effects on various disorders of the nervous system. Thus, the present study mainly focused on the influence of NAG on motor and sensory recovery after BPRA in rats and the underlying mechanisms. METHODS: Male adult Sprague Dawley (SD) rats were subjected to BPRA and reimplantation surgery and subsequently treated with NAG or saline. Behavioral tests were conducted to evaluate motor function recovery and the mechanical pain threshold of the affected forelimb. The morphological appearance of the spinal cord, musculocutaneous nerve, and biceps brachii was assessed by histological staining. Quantitative real-time PCR (qRT‒PCR) was used to measure the mRNA levels of remyelination and regeneration indicators in myocutaneous nerves. The protein levels of inflammatory and pyroptotic indicators in the spinal cord anterior horn were measured using Western blotting. RESULTS: NAG significantly accelerated the recovery of motor function in the injured forelimbs, enhanced motoneuronal survival in the anterior horn of the spinal cord, inhibited the expression of proinflammatory cytokines and pyroptosis pathway factors, facilitated axonal remyelination in the myocutaneous nerve and alleviated atrophy of the biceps brachii. Additionally, NAG attenuated neuropathic pain following BPRA. CONCLUSION: NAG promotes functional motor recovery and alleviates neuropathic pain by enhancing motoneuronal survival and axonal remyelination and inhibiting the pyroptosis pathway after BPRA in rats, laying the foundation for the use of NAG as a novel treatment for BPRA.

Inactivating Celsr2 promotes motor axon fasciculation and regeneration in mouse and human.

Understanding new modulators of axon regeneration is central to neural repair. Our previous work demonstrated critical roles of atypical cadherin Celsr2 during neural development, including cilia organization, neuron migration and axon navigation. Here, we address its role in axon regeneration. We show that Celsr2 is highly expressed in both mouse and human spinal motor neurons. Celsr2 knockout promotes axon regeneration and fasciculation in mouse cultured spinal explants. Similarly, cultured Celsr2 mutant motor neurons extend longer neurites and larger growth cones, with increased expression of end-binding protein 3 and higher potassium-induced calcium influx. Mice with Celsr2 conditional knockout in spinal motor neurons do not exhibit any behavioural deficits; however, after branchial plexus injury, axon regeneration and functional forelimb locomotor recovery are significantly improved. Similarly, knockdown of CELSR2 using shRNA interference in cultured human spinal motor explants and motor neurons increases axonal fasciculation and growth. In mouse adult spinal cord after root avulsion, in mouse embryonic spinal cords, and in cultured human motor neurons, Celsr2 downregulation is accompanied by increased levels of GTP-bound Rac1 and Cdc42, and of JNK and c-Jun. In conclusion, Celsr2 negatively regulates motor axon regeneration and is a potential target to improve neural repair.

Improved tibiofemoral contact restoration after transtibial reinsertion of the anterior root of the lateral meniscus compared to in situ repair: a biomechanical study.

PURPOSE: To compare biomechanical behaviour of the anterior root of the lateral meniscus (ARLM) after a transtibial repair (TTR) and after an in situ repair (ISR), discussing the reasons for the efficacy of the more advantageous technique. METHODS: Eight cadaveric human knees were tested at flexion angles from 0° to 90° in four conditions of their ARLM: intact, detached, reinserted using TTR, and reinserted using ISR. Specimens were subjected to 1000 N of compression, and the contact area (CA), mean pressure (MP), and peak pressure (PP) on the tibial cartilage were computed. For the TTR, traction force on the sutures was registered. RESULTS: ARLM detachment significantly altered contact biomechanics, mainly at shallow flexion. After ISR, differences compared to the healthy group persisted (extension, CA 22% smaller (p = 0.012); at 30°, CA 30% smaller (p = 0.012), MP 21%, and PP 32% higher (both p = 0.017); at 60°, CA 28% smaller (p = 0.012), MP 32%, and PP 49% higher (both p = 0.025). With TTR, alterations significantly decreased compared to the injured group, with no statistical differences from the intact ones observed, except for CA at extension (15% decrease, p = 0.012) and at 30° (12% decrease, p = 0.017). The suture tension after TTR, given as mean(SD), was 36.46(11.75)N, 44.32(11.71)N, 40.38(14.93)N, and 43.18(14.89)N for the four tested flexion angles. CONCLUSIONS: Alterations caused by ARLM detachment were partially restored with both ISR and TTR, with TTR showing better results on recovering CA, MP, and PP in the immediate postoperative period. The tensile force was far below the value reported to cause meniscal cut-out in porcine models.

Motor neuron survival is associated with reduced neuroinflammation and increased autophagy after brachial plexus avulsion injury in aldose reductase-deficient mice.

Brachial plexus root avulsion (BPRA) is frequently caused by high-energy trauma including traffic accident and birth trauma, which will induces massive motoneurons (MNs) death as well as loss of motor and sensory function in the upper limb. The death of MNs is attributed to energy deficiency, neuroinflammation and oxidative stress at the injured ventral horn of spinal cord triggered by BPRA injury. It has been reported which aldose reductase (AR), an endogenous enzyme that catalyzes fructose synthesis, positively correlates with the poor prognosis following cerebral ischemic injury, diabetic retinopathy and diabetic peripheral neuropathy. However, the role of AR in BPRA remains unknown. Herein, we used a mouse model and found that in the spinal cord of BPRA mice, the upregulation of AR correlated significantly with (1) an inactivated SIRT1-AMPK-mTOR pathway and disrupted autophagy; (2) increased byproducts accumulation of lipid peroxidation metabolism and neuroinflammation; and (3) increased MNs death. Furthermore, our results demonstrated the role of AR in BPRA injury whereby the absence of AR (AR knockout mice, AR-/-) prevented the hyper-neuroinflammation and disrupted autophagy as well as motor neuron death caused by BPRA injury. Finally, we further demonstrate that AR inhibitor epalrestat is neuroprotective against BPRA injury by increasing autophagy level, alleviating neuroinflammation and rescuing MNs death in mice. Collectively, our data demonstrate that the AR upregulation in the spinal cord is an important factor contributing to autophagy disruption, neuroinflammation and MNs death following brachial plexus roots avulsion in mice. Our study also provides a promising therapy drug to assist re-implantation surgery for the treatment of BPRA.

Lumbosacral ventral root avulsion alters reflex activation of bladder, urethra, and perineal muscles during micturition in female rabbits.

AIM: To determine the effect of the lumbosacral ventral root avulsion (VRA) on the reflex activation of bladder, urethra, and activation of perineal muscles during micturition in female rabbits. METHODS: We allocated 14 virgin female rabbits to evaluate, first, the gross anatomy of lumbosacral spinal cord root (n = 5) and, second, to determine the effect of VRA on perineal muscles during micturition (n = 9). We recorded cystometrograms, urethral pressure, and electromyograms of the bulbospongiosus (Bsm) and ischiocavernosus (Ism) muscles before and after the L6-S2 VRA. Standard variables were measured from each recording and analyzed to identify significant differences (P < .05). RESULTS: We found that the L6-S2 VRA affected directly the bladder and urethral function and reduced the duration and the frequency of the bursting of Ism and Bsm muscles during voiding. The Ism and Bsm showed a phasic activation, of different frequencies, during the voiding phase and the L6-S2 VRA inhibited the co-contraction of the Ism and Bsm-bladder-urethra. CONCLUSIONS: The Ism and Bsm are activated at different frequencies to trigger the voiding phase. The L6-S2 VRA affected the activity pattern of both perineal muscles. These modifications affected the bladder and urethra function. It is possible that the restoration of the activation frequency of perineal muscles contributed for an efficient bladder contraction.

Traumatic avulsion of the anterior medial meniscus root combined with PCL injury: a case report.

BACKGROUND: Avulsion of the anterior medial meniscus root (AMMR) has a low incidence rate, especially when it is combined with posterior cruciate ligament (PCL) injury, which hasn't been reported in any literature to date. The aim of this study was to share our experience in the diagnosis and treatment of a patient with traumatic avulsion of AMMR combined with PCL injury. CASE PRESENTATION: This article reports a 26-year-old male patient diagnosed with traumatic avulsion of the AMMR with PCL injury. After arthroscopic surgery, he achieved remission of symptoms and recovery of functions. CONCLUSIONS: Anterior meniscus root injuries are relatively rare. Its diagnosis can be made preliminarily based on clinical manifestations, physical examinations, and magnetic resonance imaging (MRI), and then confirmed by arthroscopic exploration. Arthroscopic suture anchor fixation of the injured anterior meniscus horn shows a good therapeutic effect.

l-Theanine and NEP1-40 promote nerve regeneration and functional recovery after brachial plexus root avulsion.

Brachial plexus root avulsion causes severe sequelae Treatments and prognosis face many problems, including inflammatory reaction, oxidative damage, and myelin related inhibitory effect. l-Theanine has anti-inflammatory, anti-oxidative, and neuroprotective effects. NEP1-40 competitively inhibits Nogo-66 receptor (NgR1) promotes axonal regeneration. Forty-eight Sprague-Dawley rats were randomly assigned into four groups to establish an animal model of brachial plexus root avulsion. Inflammation and oxidative damage were evaluated by spectrophotometry and motor function of the upper limbs was assessed via Terzis grooming test after modeling. Immunofluorescence and hematoxylin and eosin staining were utilized to determine the content of reactive oxygen species, activation of microglial cells, neuroprotection, and nerve regeneration. Compared with the control group, the L-Theanine + NEP1-40 group had significantly decreased myeloperoxidase, malondialdehyde, interleukin-6, reactive oxygen species, and microglial cells, significantly increased score on the Terzis grooming test, increased motor neuron content, and thickened muscle fibers, increased area, and appearance of large and clear motor endplate structures. The results of this study suggest that l-Theanine combined with NEP1-40significantly promoted nerve regeneration after brachial plexus root avulsion, and may be a potential treatment for promoting nerve regeneration. Possible mechanisms underlying these results are alleviation of oxidative damage and inflammatory responses in the injured area and antagonism of myelin inhibition.

MiR-137-3p rescue motoneuron death by targeting calpain-2.

Brachial plexus root avulsion (BPRA) is a type of injury that leads to motor function loss as a result of motoneurons (MNs) degeneration. Here we identified that the reduced expression of rat miR-137-3p in the ventral horn of spinal cord was associated with MNs death. However, the pathophysiological role of miR-137-3p in root avulsion remains poorly understood. We demonstrated that the calcium-activated neutral protease-2 (calpain-2) was a direct target gene of miR-137-3p with miR-137-3p binding to the 3'-untranslated region of calpain-2. Silencing of calpain-2 suppressed the expression of neuronal nitric oxide synthase (nNOS), a primary source of nitric oxide (NO). After avulsion 2 weeks, up-regulation of miR-137-3p in the spinal cord reduced calpain-2 levels and nNOS expression inside spinal MNs, resulting in an amelioration of the MNs death. These events provide new insight into the mechanism by which upregulation of miR-137-3p can impair MN survival in the BPRA.

[Traumatic lesions of the brachial plexus : Clinical symptoms, diagnostics and treatment]. / Traumatische Läsionen des Plexus brachialis : Klinische Symptome, Diagnostik und Therapie.

Brachial plexus lesions mostly occur in young patients as a result of high-speed accidents. They are often diagnosed and treated after a delay. This has been shown to worsen the prognosis of surgical reconstructions evidently. In 70-80% of traumatic lesions functional reinnervation can be achieved by various surgical procedures. An early sufficient diagnosis and the subsequent referral of the patient to an appropriate competence center for consultation and, if necessary, surgery are therefore essential.

Patterns of Brachial Plexus Stretch Palsy in a Prospective Series of 565 Surgically Treated Patients.

PURPOSE: To report the distribution of the different patterns of stretch brachial plexus injuries (BPIs) in a retrospective cohort of patients operated at our institution during an 11-year period. METHODS: From September 2002 to June 2012, we evaluated and operated on 565 patients with traction injuries of the brachial plexus. Average age was 26.8 years (SD ±9.3 years); the interval between the injury and surgery was 5.4 months (SD ±2.8 months). The pattern of injury was defined based on data obtained from a standardized clinical examination, preoperative helical computed tomography myelography after intradural contrast injection, surgical findings, and intraoperative electric stimulation. RESULTS: Supraclavicular injuries accounted for 91% of all cases (N = 512) whereas 9% of injuries were infraclavicular. Within the supraclavicular injuries, 50% of cases involved the entire plexus and in 12% there was avulsion of all 5 roots. Among them, 94% involved the upper plexus (C5 to C6 ± C7 ± C8), and 6% the lower plexus (C8 to T1 ± C7). C5 to C6 injuries accounted for 23% of partial BPI, C5 to C7 19%, C5 to C8 52%, C7 to T1 4%, and C8 to T1 2%. CONCLUSIONS: The most relevant findings of this study were that most panplexal BPIs showed at least one graftable root, there was a high prevalence of C5 to C8 BPI, C7 to T1 root injury was the most common pattern of lower type of injury, and infraclavicular BPI was uncommon. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV.

The current role of diagnostic imaging in the preoperative workup for refractory neonatal brachial plexus palsy.

INTRODUCTION: Despite recent improvements in perinatal care, the incidence of neonatal brachial plexus palsy (NBPP) remains relatively common. CT myelography is currently considered to be the optimal imaging modality for evaluating nerve root integrity. Recent improvements in MRI techniques have made it an attractive alternative to evaluate nerve root avulsions (preganglionic injuries). AIM: We demonstrate the utility of MRI for the evaluation of normal and avulsed spinal nerve roots. We also show the utility of ultrasound in providing useful preoperative evaluation of the postganglionic brachial plexus in patients with NBPP.

Transdiscal C6-C7 contralateral C7 nerve root transfer in the surgical repair of brachial plexus avulsion injuries.

BACKGROUND: Repair of complete brachial plexus avulsion injuries may require contralateral C7 nerve root transfer. The available techniques might allow direct neuroraphy in about 50 % of cases but the others require interposing nerve grafts or humeral shaft shortening. We aimed to see if transdiscal C6-C7 contralateral C7 nerve root transfer is technically feasible and if it allows direct coaptation with the contralateral nerve roots in 100 % of cases. METHODS: In ten fresh-frozen adult cadavers, the C7 nerve root was sectioned just before it connects with other brachial plexus branches and re-routed though the C6-C7 disc space to the contralateral side. A complete C6-C7 discectomy was performed and the disc space kept open with the aid of an autologous iliac crest bone graft. RESULTS: Transdiscal C6-C7 contralateral C7 nerve root transfer is technically feasible. In our cadavers, it provided 5.3 ± 1.2 SDcm of extra length that allowed direct coaptation with the contralateral nerve roots, mainly C8 and T1. CONCLUSIONS: Transdiscal C6-C7 contralateral C7 nerve root transfer is technically feasible. In our dissections it lengthens the available C7 nerve root stump by 5.3 ± 1.2SDcm. The increase was 4 cm versus the retropharyngeal route making direct coaptation with the contralateral C8 and T1 nerve roots possible.

Posterior lateral meniscal root tear due to a malpositioned double-bundle anterior cruciate ligament reconstruction tibial tunnel.

UNLABELLED: The posterior lateral (PL) meniscal root plays an essential role in ensuring the health of the articular cartilage of the knee joint. Injuring the PL meniscal root has been demonstrated to result in significant deleterious changes to tibiofemoral contact mechanics. Anatomic studies have reported that the posterolateral bundle of the anterior cruciate ligament (ACL) and PL root lie in close proximity on the tibial plateau. Therefore, during a double-bundle ACL reconstruction, the PL root may be inadvertently injured during the reaming of the posterior ACL double-bundle reconstruction tibial tunnel that is intended to recreate the posterolateral bundle of the ACL. This case report describes an occurrence of iatrogenic injury to the PL root due to a posteriorly malpositioned double-bundle ACL tibial tunnel. This report is the first known description of this mechanism of injury in the literature. LEVEL OF EVIDENCE: Case report, Level IV.

Down-regulation of apurinic/apyrimidinic endonuclease 1 (APE1) in spinal motor neurones under oxidative stress.

AIM: Apurinic/apyrimidinic endonuclease 1 (APE1) is an intermediate enzyme in base excision repair which is important for removing damaged nucleotides under normal and pathological conditions. Accumulation of damaged bases causes genome instability and jeopardizes cell survival. Our study is to examine APE1 regulation under oxidative stress in spinal motor neurones which are vulnerable to oxidative insult. METHODS: We challenged the motor neurone-like cell line NSC-34 with hydrogen peroxide and delineated APE1 function by applying various inhibitors. We also examined the expression of APE1 in spinal motor neurones after spinal root avulsion in adult rats. RESULTS: We showed that hydrogen peroxide induced APE1 down-regulation and cell death in a differentiated motor neurone-like cell line. Inhibiting the two functional domains of APE1, namely, DNA repair and redox domains potentiated hydrogen peroxide induced cell death. We further showed that p53 phosphorylation early after hydrogen peroxide treatment might contribute to the down-regulation of APE1. Our in vivo results similarly showed that APE1 was down-regulated after root avulsion injury in spinal motor neurones. Delay of motor neurone death suggested that APE1 might not cause immediate cell death but render motor neurones vulnerable to further oxidative insults. CONCLUSION: We conclude that spinal motor neurones down-regulate APE1 upon oxidative stress. This property renders motor neurones susceptible to continuous challenge of oxidative stress in pathological conditions.

A favourable suture method for size-mismatched nerve transfer: a case series of intercostal-to-musculocutaneous nerve transfer for brachial plexus injury.

We review a nerve suture method for size-mismatched nerve transfers and report a case series involving patients with brachial plexus injury who underwent intercostal-to-musculocutaneous nerve transfer using this method.

Brachial Plexus Root Avulsion Injury-Induced Endothelin-Converting Enzyme-Like 1 Overexpression Is Associated with Injured Motor Neurons Survival.

Brachial plexus root avulsion (BPRA) injury arises from challenging delivery during childbirth, sports-related incidents, or car accidents, leading to extensive loss of motor neurons (MNs) and subsequent paralysis, including both motor and sensory impairment. Surgical nerve re-implantation cannot effectively restore motor function, and the survival of injured MNs is vital for axon regeneration and re-innervating the target muscles. Therefore, identifying novel molecular targets to improve injured MNs survival is of great significance in the treatment of BPRA injuries. Endothelin-converting enzyme-like 1 (ECEL1), a membrane-bound metallopeptidase, was initially identified as a molecule associated with nerve injuries. Damaged neurons exhibit a significant increase in the expression of ECEL1 following various types of nerve injuries, such as optic nerve injury and sciatic nerve injury. This study aimed to investigate the relationship between ECEL1 overexpression and the survival of injured MNs following BPRA injury. Our results observed a significant elevation in ECEL1 expression in injured MNs and positively correlated with MNs survival following BPRA injury. The transcription of ECEL1 is regulated by the transcription factors c-Jun and ATF3 in the context of BPRA injury, which is consistent with previous other nerve injuries study. In addition, the expression of TrkA gradually decreases in ECEL1-positive MNs and ECEL1 possibly preserves the activity of downstream AKT-GSK3ß pathway of TrkA in injured MNs. In conclusion, our results introduce a promising therapeutic molecular target to assist re-implantation surgery for the treatment of BPRA injury.

Cervical spinal cord compression from subdural hematoma caused by traumatic nerve root avulsion: illustrative case.

BACKGROUND: Posttraumatic intradural hematomas of the cervical spine are rare findings that may yield significant neurological deficits if they compress the spinal cord. These compressive hematomas require prompt surgical evacuation. In certain instances, intradural hematomas may form from avulsion of cervical nerve roots. OBSERVATIONS: The authors present the case of a 29-year-old male who presented with right upper-extremity weakness in the setting of polytrauma after a motor vehicle accident. He had no cervical fractures but subsequently developed right lower-extremity weakness. Magnetic resonance imaging (MRI) demonstrated a compressive hematoma of the cervical spine that was initially read as an epidural hematoma. However, intraoperatively, it was found to be a subdural hematoma, eccentric to the right, stemming from an avulsion of the right C6 nerve root. LESSONS: Posttraumatic cervical subdural hematomas require rapid surgical evacuation if neurological deficits are present. The source of the hematoma may be an avulsed nerve root, and the associated deficits may be unilateral if the hematoma is eccentric to one side. Surgeons should be prepared for the possibility of an intradural hematoma even in instances in which MRI appears consistent with an epidural hematoma.

Case report: Ibogaine reduced severe neuropathic pain associated with a case of brachial plexus nerve root avulsion.

Brachial plexus nerve root avulsion results from complete separation of the nerve root from the spinal cord and is one of the most challenging types of neuropathic pain, coinciding with motor, sensory and autonomic deficits. The severe pain and typical impossibility of root reattachment often leads to requests for amputation. Ibogaine is an indole alkaloid producing psychoactive effects through reported actions upon multiple neurotransmitter systems, including NMDA, κ- and µ-opioid receptors and σ2 receptor sites, along with stimulation of neurotrophic factors GDNF and BDNF. In this case report we describe a 53-year-old male with two decades of severe intractable pain due to brachial plexus nerve root avulsion from vehicular trauma who was successfully treated with both high dose inpatient and low dose outpatient administrations of ibogaine. Though promising for future study, the adverse effects of high dose ibogaine administrations may limit tolerability of this saturation protocol to the most refractory cases.

Correlation between histopathological nerve assessment and clinical recovery in brachial plexus birth injuries.

In the management of brachial plexus birth palsies, the quality of the roots eligible for reconstruction is thought to be a key issue. The aim of the present study was to evaluate the correlations between pathological root examination and motor recovery after brachial plexus reconstructions. Quantitative histopathological analysis of intraneural fibrosis was conducted on 72 nerve transections (40 roots, 18 trunks and 14 suprascapular nerves) in 20 patients. Clinical recovery of targeted muscles after surgery was assessed by standardized functional scores. After a mean follow-up of 32 months, patients with a lower fibrosis rate for the suprascapular nerve had greater global Mallet scores (r = -0.57; p = 0.042) as well as a greater active shoulder flexion (r = -0.66; p = 0.015). Correlations were also found between C6 root and upper trunk fibrosis rate and some of the subsections of the Mallet score, active movement scale for the biceps and active elbow flexion. These results seem to confirm the relevance of intraoperative pathological evaluation of the roots and nerves after neuroma resection to optimally define the reconstruction strategy.Level of evidence: IV.

The reanimation of the elbow functions in avulsive injuries of the upper brachial plexus using the medial cord transfer: nuances of the technique and update.

OBJECTIVES: Report on a new transfer for the reinnervation of biceps and brachialis muscles after multilevel avulsive injuries of brachial plexus provided at least T1 is viable: the Medial Cord to Musculocutaneous (MCMc) and its variant, the Medial Cord to anterior Upper Trunk (MC-aUT). The MC-aUT is indicated in agenesia of musculocutaneous nerve and when a residual function in the biceps is present. The MCMc transfer would be unfeasible in the former and contraindicated in the latter. METHODS: Three hundred and five consecutive patients, classified according to the quality of hand function, are available for a long-term follow-up after reconstructive surgery. They had multiple cervical root avulsive injuries at two (C5-C6), three (C5-C6-C7) and four (C5-C6-C7-C8) levels. The reinnervation was obtained via an end-to-end transfer from two donor fascicles located in the medial cord (MC) and aimed at the flexor carpi ulnaris or the flexor digitorum profundus. RESULTS: These transfers have no failures and no complications when the hand shows a normal function. In the case of suboptimal conditions of the hand, the technique is more challenging, but still has many satisfactory results. In the four-root avulsive injuries, on the contrary, strong limitations suggest that different strategies should be preferred. EMG shows a reinnervation in both biceps and brachialis muscles and this accounts for the quality of results. Tendon transfers for wrist and finger dorsiflexion, when required, remain unencumbered. DISCUSSION: The procedures are safe, effective and easily feasible. The ideal candidate has a C5-C6 injury and a normal hand function.