Boundary cap neural crest stem cells promote angiogenesis after transplantation to avulsed dorsal roots in mice and induce migration of endothelial cells in 3D printed scaffolds.

Dorsal root avulsion injuries lead to loss of sensation and to reorganization of blood vessels (BVs) in the injured area. The inability of injured sensory axons to re-enter the spinal cord results in permanent loss of sensation, and often also leads to the development of neuropathic pain. Approaches that restore connection between peripheral sensory axons and their CNS targets are thus urgently need. Previous research has shown that sensory axons from peripherally grafted human sensory neurons are able to enter the spinal cord by growing along BVs which penetrate the CNS from the spinal cord surface. In this study we analysed the distribution of BVs after avulsion injury and how their pattern is affected by implantation at the injury site of boundary cap neural crest stem cells (bNCSCs), a transient cluster of cells, which are located at the boundary between the spinal cord and peripheral nervous system and assist the growth of sensory axons from periphery into the spinal cord during development. The superficial dorsal spinal cord vasculature was examined using intravital microscopy and intravascular BV labelling. bNCSC transplantation increased vascular volume in a non-dose responsive manner, whereas dorsal root avulsion alone did not decrease the vascular volume. To determine whether bNCSC are endowed with angiogenic properties we prepared 3D printed scaffolds, containing bNCSCs together with rings prepared from mouse aorta. We show that bNCSC do induce migration and assembly of endothelial cells in this system. These findings suggest that bNCSC transplant can promote vascularization in vivo and contribute to BV formation in 3D printed scaffolds.

Is dorsal root entry zone lesioning effective and safe for managing continuous versus paroxysmal pains post-brachial plexus avulsion?

OBJECTIVE: Patients with brachial plexus avulsion (BPA) experience chronic deafferentation pain characterized by two patterns: continuous background pain and electrical shooting paroxysmal attacks. The authors' aim was to report the effectiveness and safety of dorsal root entry zone (DREZ) lesioning in relieving the two forms of pain over short and long periods. METHODS: All patients who underwent DREZ lesioning performed by the senior author for medically refractory BPA-related pain between July 1, 2016, and June 30, 2020, in Johns Hopkins Hospital were followed up. The intensity levels for continuous and paroxysmal pains were evaluated using the numeric rating scale (NRS) preoperatively and at 4 time points postsurgery, including the day of discharge, with a mean hospital stay of 5.6 ± 1.8 days; first postoperative clinic visit (33.0 ± 15.7 days); short-term follow-up (4.0 ± 1.4 months); and long-term follow-up (3.1 ± 1.3 years). The percent of pain relief according to the NRS was categorized into excellent (≥ 75%), fair (25%-74%), and poor (< 25%). RESULTS: A total of 19 patients were included, with 4 (21.1%) lost to long-term follow-up. The mean age was 52.7 ± 13.6 years; 16 (84.2%) were men, and 10 (52.6%) had left-sided injuries. A motor vehicle accident was the most common etiology of BPA (n = 16, 84.2%). Preoperatively, all patients had motor deficits, and 8 (42.1%) experienced somatosensory deficits. The greatest pain relief was observed at the first postoperative and short-term follow-up visits, with the lowest proportions of patients having continuous pain (26.3% and 23.5%, respectively) and paroxysmal pain (5.3% and 5.9%, respectively). Also, the highest reductions in mean NRS scores were observed for first postoperative and short-term follow-up visits (continuous 1.1 ± 2.1 and 1.1 ± 2.3; paroxysms 0.4 ± 1.4 and 0.5 ± 1.7, respectively) compared to the preoperative symptomatology (continuous 6.7 ± 3.0; paroxysms 7.9 ± 4.3) (p < 0.001). Most patients had excellent relief of continuous pain (82.4% and 81.3%) and of paroxysms (90.9% and 90.0%) at the first postoperative visit and short-term follow-up visit, respectively. The pain relief benefits had diminished by 3 years after surgery but remained significantly better than in the preoperative assessment. At the last evaluation, the proportion of patients achieving excellent relief of paroxysmal pain (66.7%) was double that for continuous pain (35.7%) (p < 0.001). New sensory phenomena were observed among 10 patients (52.6%), and 1 patient developed a motor deficit. CONCLUSIONS: DREZ lesioning is an effective and safe option for relieving BPA-associated pain, with good long-term outcomes and better benefits for paroxysmal pain than for the continuous pain component.

Riluzole treatment modulates KCC2 and EAAT-2 receptor expression and Ca2+ accumulation following ventral root avulsion injury.

Avulsion injury results in motoneuron death due to the increased excitotoxicity developing in the affected spinal segments. This study focused on possible short and long term molecular and receptor expression alterations which are thought to be linked to the excitotoxic events in the ventral horn with or without the anti-excitotoxic riluzole treatment. In our experimental model the left lumbar 4 and 5 (L4, 5) ventral roots of the spinal cord were avulsed. Treated animals received riluzole for 2 weeks. Riluzole is a compound that acts to block voltage-activated Na+ and Ca2+ channels. In control animals the L4, 5 ventral roots were avulsed without riluzole treatment. Expression of astrocytic EAAT-2 and that of KCC2 in motoneurons on the affected side of the L4 spinal segment were detected after the injury by confocal and dSTORM imaging, intracellular Ca2+ levels in motoneurons were quantified by electron microscopy. The KCC2 labeling in the lateral and ventrolateral parts of the L4 ventral horn was weaker compared with the medial part of L4 ventral horn in both groups. Riluzole treatment dramatically enhanced motoneuron survival but was not able to prevent the down-regulation of KCC2 expression in injured motoneurons. In contrast, riluzole successfully obviated the increase of intracellular calcium level and the decrease of EAAT-2 expression in astrocytes compared with untreated injured animals. We conclude that KCC2 may not be an essential component for survival of injured motoneurons and riluzole is able to modulate the intracellular level of calcium and expression of EAAT-2.

Indications and Technique for the Use of Intraoperative Neuromonitoring in Brachial Plexus Surgery.

Confirming the presence or absence of a functioning nerve root in traumatic brachial plexus injuries is vital in the surgical decision-making process. Intraoperative neuromonitoring can confirm intact rootlets with the use of motor evoked potentials and somatosensory evoked potentials. The purpose of this article is to describe the rationale and details of intraoperative neuromonitoring to provide a basic understanding of its role in decision-making in patients with brachial plexus injuries.

Human dental pulp stem cell monolayer and spheroid therapy after spinal motor root avulsion in adult rats.

Spinal cord injuries result in severe neurological deficits and neuronal loss, with poor functional recovery. Mesenchymal stem cells have shown promising results; therefore the present objective of this work was to compare motor recovery after treatment with human dental pulp stem cells (hDPSC) cultivated in monolayer (2D) or as spheroids (3D), following avulsion and reimplantation of spinal motor roots in adult rats. Thus, 72 adult female Lewis rats were divided into 4 groups: avulsion (AV); avulsion followed by reimplantation (AR); avulsion associated with reimplant and 2D cell therapy (AR + 2D), and avulsion associated with reimplant and 3D cell therapy (AR + 3D). The application of the cells in 2D and 3D was performed by microsurgery, with subsequent functional assessment using a walking track test (Catwalk system), immunohistochemistry, neuronal survival, and qRT-PCR in 1-, 4-, and 12-weeks post-injury. The animals in the AR + 2D and AR + 3D groups showed the highest neuronal survival rates, and immunofluorescence revealed downregulation of GFAP, and Iba-1, with preservation of synaptophysin, indicating a reduction in glial reactivity, combined with the maintenance of pre-synaptic inputs. There was an increase in anti-inflammatory (IL-4, TGFß) and a reduction of pro-inflammatory factors (IL-6, TNFα) in animals treated with reimplantation and hDPSC. As for the functional recovery, in all analyzed parameters, the AR + 2D group performed better and was superior to the avulsion alone. Overall, our results indicate that the 2D and 3D cell therapy approaches provide successful immunomodulation and motor recovery, consistent with advanced therapies after spinal cord injury.

Neuroprotection and gliosis attenuation by intravenous application of human mesenchymal stem cells (hMSC) following ventral root crush in mice.

Rupture and stretching of spinal roots are common incidents that take place in high-energy accidents. The proximal axotomy of motoneurons by crushing of ventral roots is directly related to the degeneration of half of the lesioned population within the first two weeks. Moreover, only a small percentage of surviving motoneurons can successfully achieve regeneration after such a proximal lesion, and new treatments are necessary to improve this scenario. In this sense, mesenchymal stem cells (MSC) are of great interest once they secrete a broad spectrum of bioactive molecules that are immunomodulatory and can restore the environment after a lesion. The present work aimed at studying the effects of human mesenchymal stem cells (hMSC) therapy after ventral root crush (VRC) in mice. We evaluated motoneuron survival, glial reaction, and synapse preservation at the ventral horn. For this purpose, C57BL/6 J were submitted to a crush procedure of L4 to L6 ventral roots and treated with a single intravenous injection of adipose-derived hMSC. Evaluation of the results was carried out at 7, 14, and 28 days after injury. Analysis of motoneuron survival and astrogliosis showed that hMSC treatment resulted in higher motoneuron preservation (motoneuron survival ipsi/contralateral ratio: VRC group = 53%, VRC + hMSC group = 66%; p < 0.01), combined with reduction of astrogliosis (ipsi/contralateral GFAP immunolabeling: VRC group = 470%, VRC + hMSC group = 250%; p < 0.001). The morphological classification and Sholl analysis of microglial activation revealed that hMSC treatment reduced type V and increased type II profiles, indicating an enhancement of surveying over activated microglial cells. The glial reactivity modulation directly influenced synaptic inputs in apposition to axotomized motoneurons. In the hMSC-treated group, synaptic maintenance was increased (ipsi/contralateral synaptophysin immunolabeling: VRC group = 53%, VRC + hMSC group = 64%; p < 0.05). Overall, the present data show that intravenous injection of hMSC has neuroprotective and anti-inflammatory effects, decreasing reactive astrogliosis, and microglial reaction. Also, such cell therapy results in motoneuron preservation, combined with significant maintenance of spinal cord circuits, in particular those related to the ventral horn.

Peptide ligands targeting FGF receptors promote recovery from dorsal root crush injury via AKT/mTOR signaling.

Background: Fibroblast growth factor receptors (FGFRs) are key targets for nerve regeneration and repair. The therapeutic effect of exogenous recombinant FGFs in vivo is limited due to their high molecular weight. Small peptides with low molecular weight, easy diffusion, low immunogenicity, and nontoxic metabolite formation are potential candidates. The present study aimed to develop a novel low-molecular-weight peptide agonist of FGFR to promote nerve injury repair. Methods: Phage display technology was employed to screen peptide ligands targeting FGFR2. The peptide ligand affinity for FGFRs was detected by isothermal titration calorimetry. Structural biology-based computer virtual analysis was used to characterize the interaction between the peptide ligand and FGFR2. The peptide ligand effect on axon growth, regeneration, and behavioral recovery of sensory neurons was determined in the primary culture of sensory neurons and dorsal root ganglia (DRG) explants in vitro and a rat spinal dorsal root injury (DRI) model in vivo. The peptide ligand binding to other membrane receptors was characterized by surface plasmon resonance (SPR) and liquid chromatography-mass spectrometry (LC-MS)/MS. Intracellular signaling pathways primarily affected by the peptide ligand were characterized by phosphoproteomics, and related pathways were verified using specific inhibitors. Results: We identified a novel FGFR-targeting small peptide, CH02, with seven amino acid residues. CH02 activated FGFR signaling through high-affinity binding with the extracellular segment of FGFRs and also had an affinity for several receptor tyrosine kinase (RTK) family members, including VEGFR2. In sensory neurons cultured in vitro, CH02 maintained the survival of neurons and promoted axon growth. Simultaneously, CH02 robustly enhanced nerve regeneration and sensory-motor behavioral recovery after DRI in rats. CH02-induced activation of FGFR signaling promoted nerve regeneration primarily via AKT and ERK signaling downstream of FGFRs. Activation of mTOR downstream of AKT signaling augmented axon growth potential in response to CH02. Conclusion: Our study revealed the significant therapeutic effect of CH02 on strengthening nerve regeneration and suggested a strategy for treating peripheral and central nervous system injuries.

Dorsal Root Entry Zone Lesioning: Systematic Review

Introduction Dorsal root entry zone (DREZ) leasioning (DREZ-otomy) is considered an effective treatment for chronic pain due to spinal cord injuries, brachial and lumbosacral plexus injuries, postherpetic neuralgia, spasticity, and other conditions. The objective of the technique is to cause a selective destruction of the afferent pain fibers located in the dorsal region of the spinal cord. Objective To identify and review the effectiveness and the main aspects related to DREZ-otomy, as well as the etiologies that can be treated with it. Methods The PubMed, MEDLINE and LILACS databases were used as bases for this systematic review, having the impact factor as the selection criteria. The 23 selected publications, totalizing 1,099 patients, were organized in a table for systematic analysis. Results Satisfactory pain control was observed in 70.1% of the cases, with the best results being found in patients with brachial/lumbosacral plexus injury (70.8%) and the worst, in patients with trigeminal pain (40% to 67%). Discussion Most of the published articles observed excellent results in the control of chronic pain, especially in cases of plexus injuries. Complications are rare, and can be minimized with the use of new technologies for intraoperative monitoring and imaging. Conclusion DREZ-otomy can be considered a great alternative for the treatment of chronic pain, especially in patients who do not tolerate the side effects of the medications used in the clinical management or have refractory pain.

Does the L5 spinal nerve move? Anatomical evaluation with implications for postoperative L5 nerve palsy.

PURPOSE: While palsy of the L5 nerve root due to stretch injury is a known complication in complex lumbosacral spine surgery, the underlying pathophysiology remains unclear. The goal of this cadaveric study was to quantify movement of the L5 nerve root during flexion/extension of the hip and lower lumbar spine. METHODS: Five fresh-frozen human cadavers were dissected on both sides to expose the lumbar vertebral bodies and the L5 nerve roots. Movement of the L5 nerve root was tested during flexion and extension of the hip and lower lumbar spine. Four steps were undertaken to characterize these movements: (1) removal of the bilateral psoas muscles, (2) removal of the lumbar vertebral bodies including the transforaminal ligaments from L3 to L5, (3) opening and removing the dura mater laterally to visualize the rootlets, and (4) removal of remaining soft tissue surrounding the L5 nerve root. Two metal bars were inserted into the sacral body at the level of S1 as fixed landmarks. The tips of these bars were connected to make a line for the ruler that was used to measure movement of the L5 nerve roots. Movement was regarded as measurable when there was an L5 nerve excursion of at least 1 mm. RESULTS: The mean age at death was 86.6 years (range 68-89 years). None of the four steps revealed any measurable movement after flexion/extension of the hip and lower lumbar spine on either side (< 1 mm). Flexion of the hip and lower lumbar spine revealed lax L5 nerve roots. Extension of the hip and lower lumbar spine showed taut ones. CONCLUSION: Significant movement or displacement of the L5 nerve root could not be quantified in this study. No mechanical cause for L5 nerve palsy could be identified so the etiology of the condition remains unclear.

Neuroprotection by dimethyl fumarate following ventral root crush in C57BL/6J mice.

CNS lesions usually result in permanent loss of function and are an important problem in the medical field. In order to investigate neuroprotection/degeneration mechanisms and the synaptic plasticity of motoneurons, in addition to the potential for a variety of treatments, different experimental models of axonal injury have been proposed. Recent studies have tested the immunomodulatory drug dimethyl fumarate (DMF) for the treatment of neurodegenerative diseases and have shown promising outcomes. Therefore, in this work, we investigated the effects of DMF with regard to neuroprotection and its influence on the glial response in C57BL/6J animals subjected to crushing of the motor roots in the lumbar intumescence of the spinal cord. The animals were divided into a vehicle-treated injury group (0.08 % methylcellulose solution control group, n = 7) and injured groups treated with DMF at different doses (15, 30, 45, 90 and 180 mg/kg; n = 6-7 per dose). The 90 mg/kg dose showed the best neuroprotective results, so it was used for treatment over a period of eight weeks. Neuronal survival was assessed through Nissl staining, and functional recovery was evaluated with the CatWalk system (walking track test) and the von Frey test (mechanoreception). Immunohistochemistry was used to assess synaptic coverage and astroglial and microglial reactivity using the primary antibodies anti-synaptophysin (pre-synaptic terminal pan marker), GAD65 (GABAergic pre-synaptic terminations - inhibitory), and VGLUT1 (glutamatergic pre-synaptic terminations - excitatory). Glial reactions were evaluated with anti-IBA1 (microglia) and GFAP (astrocytes). Gene transcript levels of IL-3, IL-4, TNF-α, IL-6, TGF-ß, iNOS-M1, and arginase-M2 were quantified by RT-qPCR. The results indicated that treatment with DMF, at a dose of 90 mg/kg, promoted neuroprotection and immunomodulation towards an anti-inflammatory response. It also resulted in greater preservation of inhibitory synapses and reduced astroglial reactivity, providing a more favorable environment for sensorimotor recovery.

Calving-related intradural avulsion injuries of the thoracolumbar spinal nerve roots in a calf.

Calving difficulty may lead to traumatic peripheral nerve injury. A male, 8-mo-old, Japanese Black calf with a history of secondary dystocia as a result of fetal gigantism had lameness and gait disturbance. At autopsy, multifocal dural thickening with adhesions to the adjacent spinal cord was observed at T12-13 and L4-5 vertebral levels. Microscopically, numerous traumatic neuroma-like fascicles of nerve twigs were embedded in the dura mater with abundant collagenous connective tissue. By immunohistochemistry, axons and Schwann cells were confirmed in each nerve fascicle. Our observations suggest that avulsion injuries in the preganglionic fibers of the spinal nerve roots, and secondary spinal cord compression, resulted in the development of neurologic signs.

Quiste de Tarlov e incontinencia fecal: caso clínico y revisión de la literatura / Tarlov cyst and faecal incontinence: a case report and literature review

Los quistes de Tarlov o quistes perineurales son lesiones de las raíces nerviosas localizadas fundamentalmente en el sacro. Su etiología es incierta. Generalmente constituyen hallazgos incidentales y, por lo general, son asintomáticos. Los quistes sintomáticos son infrecuentes; los síntomas habituales suelen ser el dolor, la radiculopatía y, más raramente, las disfunciones vesicales, intestinales y sexuales. Presentamos el caso clínico de una mujer de 70 años con un quiste de Tarlov que le producía incontinencia fecal y realizamos una revisión sobre la etiología, fisiopatología y el manejo en este caso en particular

Tarlov, or perineural cysts, are lesions of the nerve root usually located at the sacral level of the spine. Their cause is unclear. These cysts are generally identified as an incidental finding and are usually asymptomatic. Symptomatic cysts are infrequent, with symptoms usually consisting of pain, radiculopathy and, less frequently, bladder, bowel and sexual dysfunction. We report the case of a 70-year-old woman with Tarlov cyst, provoking faecal incontinence, and review the aetiology, pathophysiology and management of this particular case

C5 Palsy After Cervical Spine Decompression: Topographic Correlation With C6 Chassaignac Tubercle?: A Fresh-Cadaveric Study of the Cervical Spine and Rediscussion of Etiological Hypotheses.

STUDY DESIGN: Cadaveric study on fresh unprocessed, nonpreserved, undyed specimens, which has not previously been reported. OBJECTIVE: Our aim was to explore the possible topographic correlation of the C5 nerve root with regards to its course and regional relation to C6 Chassaignac tubercle. SUMMARY OF BACKGROUND DATA: C5 palsy is reported amongst the most frequent postoperative complications of cervical spinal procedures. We hypothesized that etiologic mechanisms proposed thus far in the current literature, although with some plausible explanation, still cannot explain why the C5 nerve root and not any other level suffer a postoperative palsy. METHODS: Six fresh cadavers had extensive layer by layer dissection performed by two surgeons (one of whom has experience as an anatomy demonstrator and dissector). Roots of brachial plexus were exposed in relation to cervical transverse processes. Photographs were taken at each stage of the exposure. RESULTS: We observed a close relation of the path of the C5 nerve root with the C6 tubercle bilaterally. Moreover, we noted a steeper descent of C5 in comparison with the other adjacent roots. CONCLUSION: Steeper angle of the C5 nerve root and close proximity to C6 Chassaignac tubercle may play a role in predisposing it to neuropraxia. Detailed anatomical photographs on fresh unprocessed cadaveric specimens are novel. Peculiar anatomical features and recent experimental evidence discussed do highlight a postganglionic extraforaminal etiology corresponding well to the demographic meta-analysis data on clinical features of postoperative C5 palsy. Exploring an alternative unified "neurophysiologic stress and critical tipping point" etiological model that encompasses current theories and correlates known metanalyses observations, we believe further studies would be prudent to ascertain/refute these findings. LEVEL OF EVIDENCE: 3.

Protection of L1 nerve roots by pre-relieve tension in parallel endplate osteotomy for severe rigid thoracolumbar spine deformity.

BACKGROUND: This is a retrospective study of the use of parallel endplate osteotomy (PEO) for correction of severe rigid thoracolumbar spine deformity. METHODS: From July 2016 to January 2019, 12 patients with severe rigid thoracolumbar spine deformity underwent PEO on T12 or L1 vertebrae were studied. RESULTS: Following PEO at T12 or L1, the mean kyphosis and scoliosis correction rates reached 77.0 ± 8.9% and 75.5 ± 8.0%, respectively and the intraoperative estimated blood loss was 1950 ± 1050 mL, and the mean operative time was 6.98 ± 4.02 h. The SF-36 scores of physical function, role-physical, bodily pain, general health, vitality, social function, role-emotional and mental health changed from 63 ± 28, 50 ± 25, 50 ± 30, 34 ± 19, 53 ± 28, 45 ± 30, 30 ± 36 and 54 ± 18 at baseline to 83 ± 18, 69 ± 19, 72 ± 12, 66 ± 21, 75 ± 15, 72 ± 22, 66 ± 34 and 76 ± 12 at 1 year postoperatively, 83 ± 8, 68 ± 32, 83 ± 17, 73 ± 17, 82 ± 18, 76 ± 26, 70 ± 37 and 88 ± 12 at 18 months postoperatively, 86 ± 6, 83 ± 33, 90 ± 16, 81 ± 16, 89 ± 14, 88 ± 25, 83 ± 17 and 94 ± 10 at 24 months postoperatively, respectively (P < 0.01). Three patients had symptoms of L1 nerve root injury, as reflected by lower limb weakness and inner thigh numbness on knee extension and hip flexion, which was further confirmed by electromyography. CONCLUSIONS: PEO is easier to operate, and the spinal cord and nerve root are under direct vision and can effectively and safely correct severe rigid thoracolumbar spine deformity with satisfactory clinical results. However, it is important to identify, separate and protect L1 nerve roots during surgery in cases where patients have symptoms of back pain, muscle weakness and leg numbness on the convex side after surgery.

Complications following surgery for adolescent idiopathic scoliosis over a 13-year period.

AIMS: The purpose of this study was to evaluate the incidence and analyze the trends of surgeon-reported complications following surgery for adolescent idiopathic scoliosis (AIS) over a 13-year period from the Scoliosis Research Society (SRS) Morbidity and Mortality database. METHODS: All patients with AIS between ten and 18 years of age, entered into the SRS Morbidity and Mortality database between 2004 and 2016, were analyzed. All perioperative complications were evaluated for correlations with associated factors. Complication trends were analyzed by comparing the cohorts between 2004 to 2007 and 2013 to 2016. RESULTS: Between 2004 and 2016, a total of 84,320 patients were entered into the database. There were 1,268 patients associated with complications, giving an overall complication rate of 1.5%. Death occurred in 12 patients (0.014%). The three most commonly reported complications were surgical site infection (SSI) (441 patients; 0.52%), new neurological deficit (293; 0.35%), and implant-related complications (172; 0.20%). There was a statistically significant but weak correlation between the occurrence of a SSI and the magnitude of the primary curve (r = 0.227; p < 0.001), and blood loss in surgery (r = 0.111; p = 0.038), while the occurrence of a new neurological deficit was correlated statistically significantly but weakly with age at surgery (r = 0.147; p = 0.004) and magnitude of the primary curve (r = 0.258; p < 0.001). The overall complication rate decreased from 4.95% during 2004 to 2007 to 0.98% during 2013 to 2016 (p = 0.023). CONCLUSION: An overall complication rate of 1.5% was found in our series after surgery for AIS, with a reduction of complication rates found in the second period of the analysis. Cite this article: Bone Joint J 2020;102-B(4):519-523.

Neuroprotection in the Acute Stage Enables Functional Recovery Following Repair of Chronic Cervical Root Transection After a 3-Week Delay.

BACKGROUND: Preganglionic cervical root transection (PCRT) is the most severe type of brachial plexus injury. In some cases, surgical procedures must be postponed for ≥3 wk until electromyographic confirmation. However, research works have previously shown that treating PCRT after a 3-wk delay fails to result in functional recovery. OBJECTIVE: To assess whether the immunosuppressive drug sirolimus, by promoting neuroprotection in the acute phase of PCRT, could enable functional recovery in cases of delayed repair. METHODS: First, rats received a left 6th to 8th cervical root transection, after which half were administered sirolimus for 1 wk. Markers of microglia, astrocytes, neurons, and autophagy were assessed at days 7 and 21. Second, animals with the same injury received nerve grafts, along with acidic fibroblast growth factor and fibrin glue, 3 wk postinjury. Sirolimus was administered to half of them for the first week. Mechanical sensation, grasping power, spinal cord morphology, functional neuron survival, nerve fiber regeneration, and somatosensory-evoked potentials (SSEPs) were assessed 1 and 23 wk postinjury. RESULTS: Sirolimus was shown to attenuate microglial and astrocytic proliferation and enhance neuronal autophagy and survival; only rats treated with sirolimus underwent significant sensory and motor function recovery. In addition, rats who achieved functional recovery were shown to have abundant nerve fibers and neurons in the dorsal root entry zone, dorsal root ganglion, and ventral horn, as well as to have SSEPs reappearance. CONCLUSION: Sirolimus-induced neuroprotection in the acute stage of PCRT enables functional recovery, even if surgical repair is performed after a 3-wk delay.

Simultaneous MR neurography and apparent T2 mapping of cervical nerve roots before microendoscopic surgery to treat patient with radiculopathy due to cervical disc herniation: Preliminary results.

There is no imaging modality to quantitatively evaluate compressed cervical nerve roots in cervical radiculopathy. Here we sought to evaluate the usefulness of simultaneous apparent T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation-enhancement imaging (SHINKEI-Quant) to evaluate compressed nerves quantitatively in patients with cervical radiculopathy due to cervical disc hernia before microendoscopic surgery. One patient with cervical radiculopathy due to cervical disc hernia before microendoscopic surgery and 5 healthy subjects underwent simultaneous apparent T2 mapping and neurography with SHINKEI-Quant. The patient was a 49-year-old man with severe right upper arm pain and numbness. Based on MRI images, we suspected right C7 radiculopathy due to C6-7 cervical disc hernia. The T2 relaxation times of the cervical dorsal root ganglia of the brachial plexus bilaterally at C5-C8 were measured. We observed no significant differences in T2 relaxation times between the nerve roots on the left and right at each spinal level with values in healthy subjects. In our patient, neurography revealed swelling of the right C7 nerve, and a prolonged T2 relaxation time compared with that of the contralateral, unaffected C7 nerve. We performed microendoscopic surgery and the symptoms improved. We were able to evaluate the injured nerve root quantitatively in a patient with cervical radiculopathy using the SHINKEI-Quant technique, being the first study to our knowledge to show the usefulness of this technique to evaluate cervical radiculopathy quantitatively before microendoscopic surgery.

Nerve transfer for restoration of lower motor neuron-lesioned bladder and urethra function: establishment of a canine model and interim pilot study results.

OBJECTIVE: Previous patient surveys have shown that patients with spinal cord or cauda equina injuries prioritize recovery of bladder function. The authors sought to determine if nerve transfer after long-term decentralization restores bladder and sphincter function in canines. METHODS: Twenty-four female canines were included in this study. Transection of sacral roots and hypogastric nerves (S Dec) was performed in 6 animals, and 7 animals underwent this procedure with additional transection of the L7 dorsal roots (L7d+S Dec). Twelve months later, 3 L7d+S Dec animals underwent obturator-to-pelvic nerve and sciatic-to-pudendal nerve transfers (L7d+S Dec+Reinn). Eleven animals served as controls. Squat-and-void behaviors were tracked before and after decentralization, after reinnervation, and following awake bladder-filling procedures. Bladders were cystoscopically injected with Fluoro-Gold 3 weeks before euthanasia. Immediately before euthanasia, transferred nerves were stimulated to evaluate motor function. Dorsal root ganglia were assessed for retrogradely labeled neurons. RESULTS: Transection of only sacral roots failed to reduce squat-and-void postures; L7 dorsal root transection was necessary for significant reduction. Three L7d+S Dec animals showing loss of squat-and-void postures post-decentralization were chosen for reinnervation and recovered these postures 4-6 months after reinnervation. Each showed obturator nerve stimulation-induced bladder contractions and sciatic nerve stimulation-induced anal sphincter contractions immediately prior to euthanasia. One showed sciatic nerve stimulation-induced external urethral sphincter contractions and voluntarily voided twice following nonanesthetized bladder filling. Reinnervation was confirmed by increased labeled cells in L2 and the L4-6 dorsal root ganglia (source of obturator nerve in canines) of L7d+S Dec+Reinn animals, compared with controls. CONCLUSIONS: New neuronal pathways created by nerve transfer can restore bladder sensation and motor function in lower motor neuron-lesioned canines even 12 months after decentralization.

Berberine enhances survival and axonal regeneration of motoneurons following spinal root avulsion and re-implantation in rats.

Brachial plexus avulsion (BPA) occurs when the spinal nerve roots are pulled away from the surface of the spinal cord and disconnects neuronal cell body from its distal downstream axon, which induces massive motoneuron death, motor axon degeneration and de-innervation of targeted muscles, thereby resulting in permanent paralysis of motor functions in the upper limb. Avulsion injury triggers oxidative stress and intense local neuroinflammation at the lesioned site, leading to the death of most motoneurons. Berberine (BBR), a natural isoquinoline alkaloid derived from medicinal herbs of Berberis and Coptis species, has been reported to possess neuro-protective, anti-inflammatory and anti-oxidative effects in various animal models of central nervous system (CNS)-related disorders. In this study, we aimed to investigate the effect of BBR on motoneuron survival and axonal regeneration following spinal root avulsion plus re-implantation in rats. Our results indicated BBR significantly accelerated motor function recovery in the forelimb as revealed by the increased Terzis grooming test score, facilitated motor axon regeneration as evidenced by the elevated number of Fluoro-Gold-labeled and P75-positive regenerative motoneurons. The survival of motoneurons was notably promoted by BBR administration presented with boosted ChAT-immunopositive and neutral red-stained neurons. BBR treatment efficiently alleviated muscle atrophy, attenuated functional motor endplates loss in biceps and prevented the reduction of motor axons in the musculocutaneous nerve. Additionally, BBR treatment markedly mitigated the avulsion-induced neuroinflammation via inhibiting microglial and astroglial reactivity, up-regulated the expression of antioxidative indicator Cu/Zn SOD, and down-regulated the levels of nNOS, 3-NT, lipid peroxidation and NF-κB, as well as promoted SIRT1, PI3K and Akt activation. Collectively, BBR might be a promising therapy to assist re-implantation surgery for the treatment of BPA.