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Introduction: Spinal cord injury (SCI) is a devastating injury and remains one of the largest medical and social burdens because of its intractable nature. According to the recent advances in stem cell biology, the possibility of spinal cord regeneration and functional restoration has been suggested by introducing appropriate stem cells. Multilineage-differentiating stress enduring (Muse) cells are a type of nontumorigenic endogenous reparative stem cell. The positive results of Muse cell transplantation for SCI was shown previously. As a first step for clinical application in human SCI, we conducted a clinical trial aiming to confirm the safety and feasibility of intravenously injected donor-Muse cells., Methods: The study design of the current trial was a prospective, multicenter, nonrandomized, nonblinded, single-arm study. The clinical trial registration number was JRCT1080224764. Patients with a cervical SCI with a neurological level of injury C4 to C7 with the severity of modified Frankel classification B1 and B2 were included. A primary endpoint was set for safety and feasibility. Our protocol was approved by the PMDA, and the trial was funded by the Life Science Institute, Tokyo, Japan. The present clinical trial recruited 10 participants (8 males and 2 females) with an average age of 49.3 ± 21.2 years old. All 10 participants received a single dose of allogenic CL2020 (a total of 15 × 10 6 cells, 2.1-2.7 × 10 5 cells/kg of body weight), which is a Muse cell-based product produced from human mesenchymal stem cells, by an intravenous drip., Results: There were two reported severe adverse events, both of which were determined to have no causal relationship with Muse cell treatment. The change in the ISNCSCI motor score, the activity of daily living and quality of life scores showed statistically significant improvements compared to those data at the time of CL2020 administration., Conclusion: In the present trial, no safety concerns were identified, and Muse cell product transplantation demonstrated good tolerability. Future clinical trials with appropriate study designs incorporating a control arm will clarify the definitive efficacy of single-dose allogenic Muse cell treatment with intravenous administration to treat SCI., Trial Registration: jRCT, JRCT1080224764. Registered 03 July 2019, https://jrct.niph.go.jp/latest-detail/jRCT1080224764 ., (© 2024. The Author(s).)

Study Design: Retrospective cohort study., Objectives: To define the prognosis and predictive factors for neurological improvement in older patients with incomplete spinal cord injury (SCI) of American Spinal Injury Association Impairment Scale grade C (AIS-C)., Settings: Multi-institutions in Japan., Methods: We included patients aged ≥65 years with traumatic SCI of AIS-C who were treated conservatively or surgically with >3 follow-up months. To identify factors related to neurological improvement, patients were divided into three groups according to their neurological status at the final follow-up, with univariate among-group comparisons of demographics, radiographic, and therapeutic factors. Significant variables were included in the multivariate logistic regression analysis., Results: Overall, 296 older patients with SCI of AIS-C on admission were identified (average age: 75.2 years, average follow-up: 18.7 months). Among them, 190 (64.2%) patients improved to AIS-D and 21 (7.1%) patients improved to AIS-E at final follow-up. There were significant among-group differences in age (p = 0.026), body mass index (p = 0.007), status of pre-traumatic activities of daily living (ADL) (p = 0.037), and serum albumin concentrations (p = 0.011). Logistic regression analysis showed no significant differences in variables in the stratified group of patients who improved to AIS-D. Meanwhile, serum albumin was a significant variable in patients who improved to AIS-E (p = 0.026; OR: 6.20, pre-traumatic ADL was omitted due to data skewness)., Conclusions: Most older patients with incomplete AIS-C SCI demonstrated at least 1 grade of neurological improvement. However, <10% of patients achieved complete recovery. Key predictors of complete recovery were high serum albumin levels on admission and independent pre-traumatic ADL., Sponsorship: No funding was received for this study., (© 2024. The Author(s), under exclusive licence to International Spinal Cord Society.)

This retrospective cohort study established malnutrition's impact on mortality and neurological recovery of older patients with cervical spinal cord injury (SCI). It included patients aged ≥ 65 years with traumatic cervical SCI treated conservatively or surgically. The Geriatric Nutritional Risk Index was calculated to assess nutritional-related risk. Overall, 789 patients (mean follow-up: 20.1 months) were examined and 47 had major nutritional-related risks on admission. One-year mortality rate, median survival time, neurological recovery, and activities of daily living (ADL) at 1 year post-injury were compared between patients with major nutrition-related risk and matched controls selected using 1:2 propensity score matching to adjust for age, pre-traumatic neurological impairment, and activity. In the Kaplan-Meier analysis, the median survival times were 44.9 and 76.5 months for patients with major nutrition-related risk and matched controls, respectively (p = 0.015). Matched controls had more individuals with a neurological improvement of American Spinal Injury Association Impairment Scale ≥ 1 grade (p = 0.039) and independence in ADL at 1 year post-injury than patients with major nutrition-related risk (p < 0.05). In conclusion, 6% of older patients with cervical SCI had major nutrition-related risks; they showed a significantly higher 1 year mortality rate, shorter survival time, poorer neurological improvement, and lower ADL at 1 year post-injury than matched controls., (© 2024. The Author(s).)

Background: Although previous studies have demonstrated the advantages of early surgery for traumatic spinal cord injury (SCI), the appropriate surgical timing for cervical SCIs (CSCIs) without bone injury remains controversial. Here, we investigated the influence of relatively early surgery within 48 h of injury on the neurological recovery of elderly patients with CSCI and no bone injury., Methods: In this retrospective multicenter study, we reviewed data from 159 consecutive patients aged ≥65 years with CSCI without bone injury who underwent surgery in participating centers between 2010 and 2020. Patients were followed up for at least 6 months following CSCI. We divided patients into relatively early (≤48 h after CSCI, n = 24) and late surgery (>48 h after CSCI, n = 135) groups, and baseline characteristics and neurological outcomes were compared between them. Multivariate analysis was performed to identify factors associated with neurological recovery., Results: The relatively early surgery group demonstrated a lower prevalence of cardiac disease, poorer baseline American Spinal Injury Association (ASIA) impairment scale grade, and lower baseline ASIA motor score (AMS) than those of the late surgery group (P < 0.030, P < 0.001, and P < 0.001, respectively). Although the AMS was lower in the relatively early surgery group at 6 months following injury (P = 0.001), greater improvement in this score from baseline to 6-months post injury was observed (P = 0.010). Multiple linear regression analysis revealed that relatively early surgery did not affect postoperative improvement in AMS, rather, lower baseline AMS was associated with better AMS improvement (P < 0.001). Delirium (P = 0.006), pneumonia (P = 0.030), and diabetes mellitus (P = 0.039) negatively influenced postoperative improvement., Conclusions: Although further validation by future studies is required, relatively early surgery did not show a positive influence on neurological recovery after CSCI without bone injury in the elderly., (Copyright © 2023 The Japanese Orthopaedic Association. All rights reserved.)

Purpose: To investigate the impact of early post-injury respiratory dysfunction for neurological and ambulatory ability recovery in patients with cervical spinal cord injury (SCI) and/or fractures., Methods: We included 1,353 elderly patients with SCI and/or fractures from 78 institutions in Japan. Patients who required early tracheostomy and ventilator management and those who developed respiratory complications were included in the respiratory dysfunction group, which was further classified into mild and severe respiratory groups based on respiratory weaning management. Patient characteristics, laboratory data, neurological impairment scale scores, complications at injury, and surgical treatment were evaluated. We performed a propensity score-matched analysis to compare neurological outcomes and mobility between groups., Results: Overall, 104 patients (7.8%) had impaired respiratory function. In propensity score-matched analysis, the respiratory dysfunction group had a lower home discharge and ambulation rates (p = 0.018, p = 0.001, respectively), and higher rate of severe paralysis (p < 0.001) at discharge. At the final follow-up, the respiratory dysfunction group had a lower ambulation rate (p = 0.004) and higher rate of severe paralysis (p < 0.001). Twenty-six patients with severe disability required respiratory management for up to 6 months post-injury and died of respiratory complications. The mild and severe respiratory dysfunction groups had a high percentage of severe paraplegic cases with low ambulatory ability; there was no significant difference between them. The severe respiratory dysfunction group tended to have a poorer prognosis., Conclusion: Respiratory dysfunction in elderly patients with SCI and/or cervical fracture in the early post-injury period reflects the severity of the condition and may be a useful prognostic predictor., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Although the incidence of cervical spinal cord injury (CSCI) with ossification of the posterior longitudinal ligament (OPLL) has increased in older adults, its etiology and neurological outcomes remain unknown. We identified OPLL characteristics and determined whether they influence neurological severity and improvement of CSCI in older patients. This multicenter retrospective cohort study identified 1512 patients aged ≥ 65 years diagnosed with CSCI on admission during 2010-2020. We analyzed CSCI etiology in OPLL patients. We performed propensity score-adjusted analyses to compare neurological outcomes between patients with and without OPLL. Cases were matched based on variables influencing neurological prognosis. The primary neurological outcome was rated according to the American Spine Injury Association (ASIA) impairment scale (AIS) and ASIA motor score (AMS). In 332 OPLL patients, the male-to-female ratio was approximately 4:1. Half of all patients displayed low-energy trauma-induced injury and one-third had CSCI without a bony injury. Propensity score matching created 279 pairs. There was no significant difference in the AIS grade and AMS between patients with and without OPLL during hospitalization, 6 months, and 12 months following injury. OPLL patients tended to exhibit worse neurological findings during injury; nevertheless, OPLL was not associated with poor neurological improvement in older CSCI patients., (© 2023. The Author(s).)

Study Design: Biomechanical study., Objective: Cervical ossification of the posterior longitudinal ligament (C-OPLL) causes myelopathy. Though posterior decompression for C-OPLL showed positive results, poor outcomes were seen in patients with a kyphotic alignment. Posterior decompression with fusion (PDF) tends to show better results compared to posterior decompression. The aim of this study is to evaluate the effects of the posterior procedures for C-OPLL., Setting: Yamaguchi University., Methods: Based on 3D finite element C2-C7 spine created from medical images and a spinal cord, the following compression models were created: the intact model, K-line 0 mm model, and K-line 2 mm model. These models were used to analyze the effects of posterior decompression with varied lengths of fixation. The stress of the spinal cord was calculated for intact, K-line 0 mm, and K-line 2 mm as preoperative models, and laminectomy (LN)-K-line 0 mm, PDF (C4-C5)-K-line 0 mm, PDF (C3-C6)-K-line 0 mm, LN-K-line 2 mm, PDF (C4-C5)-K-line 2 mm, and PDF (C3-C6)-K-line 2 mm model as operative models in a neutral, flexion, and extension., Results: As the compression increased, stress on the spinal cord increased compared to the intact model. In the neutral, posterior decompression decreased the stress of the spinal cord. However, in flexion and extension, the stress on the spinal cord for LN-K-line 0 or 2 mm, PDF (C4-C5)-K-line 0 or 2 mm, and PDF (C3-C6)-K-line 0 or 2 mm models decreased by more than 40%, 43%, and 70% respectively compared to the K-line 0 or 2 mm model., Conclusions: In kyphotic C-OPLL, it is essential to control intervertebral mobility in the posterior approach., (© 2022. The Author(s), under exclusive licence to International Spinal Cord Society.)

Spinal cord injury (SCI) is a catastrophic condition associated with significant neurological deficit and social and financial burdens. It is currently being managed symptomatically, with no real therapeutic strategies available. In recent years, a number of innovative regenerative strategies have emerged and have been continuously investigated in preclinical research and clinical trials. In the near future, several more are expected to come down the translational pipeline. Among ongoing and completed trials are those reporting the use of biomaterial scaffolds. The advancements in biomaterial technology, combined with stem cell therapy or other regenerative therapy, can now accelerate the progress of promising novel therapeutic strategies from bench to bedside. Various types of approaches to regeneration therapy for SCI have been combined with the use of supportive biomaterial scaffolds as a drug and cell delivery system to facilitate favorable cell-material interactions and the supportive effect of neuroprotection. In this review, we summarize some of the most recent insights of preclinical and clinical studies using biomaterial scaffolds in regenerative therapy for SCI and summarized the biomaterial strategies for treatment with simplified results data. One hundred and sixty-eight articles were selected in the present review, in which we focused on biomaterial scaffolds. We conducted our search of articles using PubMed and Medline, a medical database. We used a combination of "Spinal cord injury" and ["Biomaterial", or "Scaffold"] as search terms and searched articles published up until 30 April 2022. Successful future therapies will require these biomaterial scaffolds and other synergistic approaches to address the persistent barriers to regeneration, including glial scarring, the loss of a structural framework, and biocompatibility. This database could serve as a benchmark to progress in future clinical trials for SCI using biomaterial scaffolds.

Study Design: Retrospective multicenter study., Objectives: To investigate the neurological outcomes of older individuals treated with surgery versus conservative treatment for cervical spinal cord injury (CSCI) without bone injury., Setting: Thirty-three medical institutions in Japan., Methods: This study included 317 consecutive persons aged ≥65 years with CSCI without bone injury in participating institutes between 2010 and 2020. The participants were followed up for at least 6 months after the injury. Individuals were divided into surgery (n = 114) and conservative treatment (n = 203) groups. To compare neurological outcomes and complications between the groups, propensity score matching of the baseline factors (characteristics, comorbidities, and neurological function) was performed., Results: After propensity score matching, the surgery and conservative treatment groups comprised 89 individuals each. Surgery was performed at a median of 9.0 (3-17) days after CSCI. Baseline factors were comparable between groups, and the standardized difference in the covariates in the matched cohort was <10%. The American Spinal Injury Association (ASIA) impairment scale grade and ASIA motor score (AMS) 6 months after injury and changes in the AMS from baseline to 6 months after injury were not significantly different between groups (P = 0.63, P = 0.24, and P = 0.75, respectively). Few participants who underwent surgery demonstrated perioperative complications such as dural tear (1.1%), surgical site infection (2.2%), and C5 palsy (5.6%)., Conclusion: Conservative treatment is suggested to be a more favorable option for older individuals with CSCI without bone injuries, but this finding requires further validation., (© 2022. The Author(s), under exclusive licence to International Spinal Cord Society.)

Background: The 1-year mortality and functional prognoses of patients who received surgery for cervical trauma in the elderly remains unclear. The aim of this study is to investigate the rates of, and factors associated with mortality and the deterioration in walking capacity occurring 1 year after spinal fusion surgery for cervical fractures in patients 65 years of age or older., Methods: Three hundred thirteen patients aged 65 years or more with a traumatic cervical fracture who received spinal fusion surgery were enrolled. The patients were divided into a survival group and a mortality group, or a maintained walking capacity group and a deteriorated walking capacity group. We compared patients' backgrounds, trauma, and surgical parameters between the two groups. To identify factors associated with mortality or a deteriorated walking capacity 1 year postoperatively, a multivariate logistic regression analysis was conducted., Results: One year postoperatively, the rate of mortality was 8%. A higher Charlson comorbidity index (CCI) score, a more severe the American Spinal Cord Injury Association impairment scale (AIS), and longer surgical time were identified as independent factors associated with an increase in 1-year mortality. The rate of deterioration in walking capacity between pre-trauma and 1 year postoperatively was 33%. A more severe AIS, lower albumin (Alb) and hemoglobin (Hb) values, and a larger number of fused segments were identified as independent factors associated with the increased risk of deteriorated walking capacity 1 year postoperatively., Conclusions: The 1-year rate of mortality after spinal fusion surgery for cervical fracture in patients 65 years of age or older was 8%, and its associated factors were a higher CCI score, a more severe AIS, and a longer surgical time. The rate of deterioration in walking capacity was 33%, and its associated factors were a more severe AIS, lower Alb, lower Hb values, and a larger number of fused segments., (© 2022. The Author(s).)

Chronic spinal cord injury (SCI) is a catastrophic condition associated with significant neurological deficit and social and financial burdens. It is currently being managed symptomatically with no real therapeutic strategies available. In recent years, a number of innovative regenerative strategies have emerged and have been continuously investigated in clinical trials. In addition, several more are coming down the translational pipeline. Among ongoing and completed trials are those reporting the use of mesenchymal stem cells, neural stem/progenitor cells, induced pluripotent stem cells, olfactory ensheathing cells, and Schwann cells. The advancements in stem cell technology, combined with the powerful neuroimaging modalities, can now accelerate the pathway of promising novel therapeutic strategies from bench to bedside. Various combinations of different molecular therapies have been combined with supportive scaffolds to facilitate favorable cell-material interactions. In this review, we summarized some of the most recent insights into the preclinical and clinical studies using stem cells and other supportive drugs to unlock the microenvironment in chronic SCI to treat patients with this condition. Successful future therapies will require these stem cells and other synergistic approaches to address the persistent barriers to regeneration, including glial scarring, loss of structural framework, and immunorejection.

Objective: The correlation between the progression of spinal cord lesions using spinal cord evoked potentials (SCEPs) and neurological findings are unclear. The purpose is to electrophysiologically evaluate relative vulnerability of spinal cord in patients with compressive cervical myelopathy (CCM) at C4-C5 intervertebral level using SCEPs and correlate the progression of spinal cord lesions with neurological findings. Design: Retrospective study. Setting: Yamaguchi University Hospital. Participants: 36 patients. Methods: SCEPs following median nerve stimulation (MN-SCEPs), ulnar nerve stimulation (UN-SCEPs), transcranial electric stimulation (TCE-SCEPs), and spinal cord stimulation (SC-SCEPs) were intraoperatively recorded. MN-SCEPs are mediated by posterior horns (4, 5 layers), UN-SCEPs by the Burdach tract, TCE-SCEPs by the lateral corticospinal tract, and SC-SCEPs by the Goll tract. We evaluated the neurological findings (numbness, tactile sense and pain sense in the C6 area, tactile sense in the lower extremities, and triceps tendon reflex [TTR]). Results: The incidence of electrophysiological and clinical abnormalities decreased in the order of UN-SCEPs (100%), TCE-SCEPs (94.4%), MN-SCEPs (77.8%), and SC-SCEPs (69.4%), and in the order of numbness (100%), pain sense (97.2%), TTR (91.7%), tactile sense in the C6 area (83.3%), and tactile sense in the lower extremities (70.0%), respectively. Conclusions: The relative vulnerability of spinal cord occurred in the order of the Burdach tract, the lateral corticospinal tract, posterior horns (4, 5 layers), and the Goll tract in most patients with CCM at the C4-C5 intervertebral level.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To investigate factors associated with excellent outcomes after conservative treatment in patients with proximal cervical spondylotic amyotrophy (CSA) using electrophysiological, radiological, and neurological findings. Design: Retrospective study. Setting: Yamaguchi University Hospital. Participants: Seventy-seven patients. Interventions: Erb-point-stimulated compound muscle action potentials (CMAP) were recorded in deltoid and biceps. The percentages of CMAP amplitudes on the affected side compared to the normal side in deltoid (PD) and biceps brachii (PB) were calculated. Central motor conduction time was calculated by subtracting peripheral motor conduction time from the onset latency of motor evoked potentials. Cervical lordotic angles, the diameter of C5 canal, and the intervertebral range at C4-C5 and C5-C6 levels were assessed on plain radiographs. Magnetic resonance imaging was used to assess the width of the intervertebral foramen (WIF) at C4-C5 and C5-C6 levels in the axial views. First visit and final follow-up strengths of most atrophic muscles were evaluated using manual muscle testing (MMT). Improvements in strength were classified as excellent (five grades recovered), good (more than one grade recovered), unchanged (no improvement), or poor (worsened). Results: The outcomes were excellent in 27 patients (35.1%), good in 22 (28.6%), unchanged in 26 (33.8%), and poor in two (2.5%). Factors associated with excellent outcomes were WIF at C4-C5 and C5-C6 on the normal side, PB, and CMAP amplitudes of the deltoid on the normal side. Conclusions: Patients with excellent outcomes originally had wide WIF at C4-C5 and C5-C6 levels and the absence of symptomatic spinal cord compression at C3-C4 and C4-C5 levels.

Introduction: Granulocyte colony-stimulating factor (G-CSF) is generally used for neutropaenia. Previous experimental studies revealed that G-CSF promoted neurological recovery after spinal cord injury (SCI). Next, we moved to early phase of clinical trials. In a phase I/IIa trial, no adverse events were observed. Next, we conducted a non-randomised, non-blinded, comparative trial, which suggested the efficacy of G-CSF for promoting neurological recovery. Based on those results, we are now performing a phase III trial., Methods and Analysis: The objective of this study is to evaluate the efficacy of G-CSF for acute SCI. The study design is a prospective, multicentre, randomised, double-blinded, placebo-controlled comparative study. The current trial includes cervical SCI (severity of American Spinal Injury Association (ASIA) Impairment Scale B/C) within 48 hours after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group is administered 400 µg/m 2 /day×5 days of G-CSF in normal saline via intravenous infusion for 5 consecutive days. The placebo group is similarly administered a placebo. Our primary endpoint is changes in ASIA motor scores from baseline to 3 months. Each group includes 44 patients (88 total patients)., Ethics and Dissemination: The study will be conducted according to the principles of the World Medical Association Declaration of Helsinki and in accordance with the Japanese Medical Research Involving Human Subjects Act and other guidelines, regulations and Acts. Results of the clinical study will be submitted to the head of the respective clinical study site as a report after conclusion of the clinical study by the sponsor-investigator. Even if the results are not favourable despite conducting the clinical study properly, the data will be published as a paper., Trial Registration Number: UMIN000018752., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Central motor conduction time (CMCT) recorded from the abductor pollicis brevis (CMCT-APB) and abductor digiti minimi (CMCT-ADM) muscles may enable the evaluation of patients with C6-7 myelopathy. CMCT is more useful for the evaluation of the function of spinal cord than magnetic resonance imaging (MRI) findings. CMCT may be associated with age and height. However, there are few reports regarding CMCT-APB in normal subjects. This study aimed to investigate the relationships between age, height, and conduction parameters in normal subjects to assess the effectiveness of using CMCT-APB and CMCT-ADM for the evaluation of patients with C6-7 and C7-T1 myelopathy., Design: Retrospective study., Methods: Fifteen patients with cervical compressive myelopathy at C6-7 (11 patients) or C7-T1 (4 patients) level were enrolled. The control group consisted of 150 normal subjects (mean age 45.8±17.0 years; mean height 163.6±8.9 cm). Motor evoked potentials induced by transcranial magnetic stimulation and F-waves were used to determine CMCT., Outcome Measures: CMCT-APB, CMCT-ADM., Results: The normative values of CMCT-APB and CMCT-ADM were 5.3±0.7 ms and 5.2±0.8 ms, respectively. CMCT-APB was significantly longer than CMCT-ADM for patients with C6-7 myelopathy (P < 0.05). Neither of the CMCTs for those with C7-T1 myelopathy were significantly different from those of controls, but CMCT-APB was more prolonged than CMCT-ADM in patients with C6-C7 myelopathy., Conclusions: CMCTs improve the accuracy of the diagnosis of myelopathy by pinpointing the lesion in combination with MRI imaging. Selective CMCT-APB prolongation may be seen in patients with C6-7 myelopathy but not C7-T1 myelopathy.

Traumatic spinal cord injuries (SCIs) affect millions of people worldwide; the majority of whom are in the chronic phase of their injury. Unfortunately, most current treatments target the acute/subacute injury phase as the microenvironment of chronically injured cord consists of a well-established glial scar with inhibitory chondroitin sulfate proteoglycans (CSPGs) which acts as a potent barrier to regeneration. It has been shown that CSPGs can be degraded in vivo by intrathecal Chondroitinase ABC (ChABC) to produce a more permissive environment for regeneration by endogenous cells or transplanted neural stem cells (NSCs) in the subacute phase of injury. Using a translationally-relevant clip-contusion model of cervical spinal cord injury in mice we sought to determine if ChABC pretreatment could modify the harsh chronic microenvironment to enhance subsequent regeneration by induced pluripotent stem cell-derived NSCs (iPS-NSC). Seven weeks after injury-during the chronic phase-we delivered ChABC by intrathecal osmotic pump for one week followed by intraparenchymal iPS-NSC transplant rostral and caudal to the injury epicenter. ChABC administration reduced chronic-injury scar and resulted in significantly improved iPSC-NSC survival with clear differentiation into all three neuroglial lineages. Neurons derived from transplanted cells also formed functional synapses with host circuits on patch clamp analysis. Furthermore, the combined treatment led to recovery in key functional muscle groups including forelimb grip strength and measures of forelimb/hindlimb locomotion assessed by Catwalk. This represents important proof-of-concept data that the chronically injured spinal cord can be 'unlocked' by ChABC pretreatment to produce a microenvironment conducive to regenerative iPS-NSC therapy.

Traumatically injured spinal cord (SC) displays structural damage that includes discontinuity of long tracts and cavitations. Axonal regrowth beyond the lesion is necessary to achieve functional recovery following SC injury. We report here the development of an artificial collagen-filament (CF) scaffold to replace the SC in 8-week-old female Fisher rats. Axonal sprouting and regrowth was very rapid following grafting of the CF. One week after implantation, the scaffold was filled with cells of host origin and with regenerated axons. Histological examination of SC adjacent to the scaffold showed little cavity formation or fibrous scarring. Eight weeks after implantation, myelinated nerve fibers were found in the scaffold and 10-25 % of rubrospinal tracts were repaired. Four to six weeks after transplantation, motor evoked potentials were recorded in CF-grafted rats but were not detectable in non-grafted rats. Electrophysiological and histological examinations revealed the grafted CF was likely to function as a nerve tract. In addition, these results suggest that collagen fibers may provide a permissive microenvironment for the elongation of SC axons and to support the process of spinal cord regeneration.

Background: Rehabilitation facilitates the reorganization of residual/regenerated neural pathways and is key in improving motor function following spinal cord injury. Neuromuscular electrical stimulation (NMES) has been reported as being clinically effective. Although it can be used after the acute phase post-injury, the optimal stimulation conditions to improve motor function remain unclear. In this paper, we examined the effectiveness of NMES with alternating currents in the kilohertz (kHz) frequency in gait rhythm stimulation therapy., Methods: Tests were performed using 20 mature female Fischer rats. Incomplete spinal cord injuries (T9 level) were made with an IH impactor using a force of 150 kdyn, and NMES was administered for 3 days from the 7th day post-injury. The needle electrodes were inserted percutaneously near the motor point of each muscle in conscious rats, and each muscle on the left and right leg was stimulated for 15 min at two frequencies, 75 Hz and 8 kHz, to induce a gait rhythm. Motor function was evaluated using Basso, Beattie, Bresnahan (BBB) scores and three-dimensional (3D) gait analysis. Rats were divided into four groups (5 rats/group), including the NMES treatment 75-Hz group (iSCI-NMES 75 Hz), 8-kHz group (iSCI-NMES 8 kHz), injury control group (iSCI-NT), and normal group (Normal-CT), and were compared., Results: There was no significant difference in BBB scores among the three groups. In 3D gait analysis, compared with the injury control group, the 8-kHz group showed a significant improvement in synergistic movement of both hindlimbs., Conclusion: We suggest that kHz stimulation is effective in gait rhythm stimulation using NMES.

While neural stem/progenitor cells (NPCs) show promise for traumatic spinal cord injury (SCI), their efficacy in cervical SCI remains to be established. Moreover, their application to SCI is limited by the challenges posed by the lesion including the glial scar and the post-traumatic cavitation. Given this background, we sought to examine the synergistic effect of self-assembling peptide (SAP) molecules, designed to optimize the post-traumatic CNS microenvironment, and NSCs in a clinically-relevant model of contusive/compressive cervical SCI. We injected K2(QL)6K2 (QL6) SAPs into the lesion epicenter 14 days after bilateral clip compression-induced cervical SCI in rats, combined with simultaneous transplantation of neural stem/progenitor cells (NPCs) intraspinally adjacent to the lesion epicenter. The QL6 SAPs reduced the volume of cystic cavitation in the spinal cord lesion. Simultaneously engrafted NPCs preserved motor neurons and attenuated perilesional inflammation. The combination of QL6 and NPCs promoted forelimb neurobehavioral recovery and was associated with significant improvement in forelimb print area and stride length. In summary, we report for the first time histologic and functional benefits in a clinically-relevant model of cervical SCI through the synergistic effects of combined SAP and NPCs., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Combination therapy is essential for functional repairs of the spinal cord. Rehabilitative therapy can be considered as the key for reorganizing the nervous system after spinal cord regeneration therapy. Functional electrical stimulation has been used as a neuroprosthesis in quadriplegia and can be used for providing rehabilitative therapy to tap the capability for central nervous system reorganization after spinal cord regeneration therapy., Objective: To develop a less invasive muscular electrical stimulation model capable of being combined with spinal cord regeneration therapy especially for motor therapy in the acute stage after spinal cord injury., Methods: The tibialis anterior and gastrocnemius motor points were identified in intact anesthetized adult female Fischer rats, and stimulation needle electrodes were percutaneously inserted into these points. Threshold currents for visual twitches were obtained upon stimulation using pulses of 75 or 8 kHz for 200 ms. Biphasic pulse widths of 20, 40, 80, 100, 300, and 500 µs per phase were used to determine strength-duration curves. Using these parameters and previously obtained locomotor electromyogram data, stimulations were performed on bilateral joint muscle pairs to produce reciprocal flexion/extension movements of the ankle for 15 minutes while three-dimensional joint kinematics were assessed., Results: Rhythmic muscular electrical stimulation with needle electrodes was successfully done, but decreased range of motion (ROM) over time. High-frequency and high-amplitude stimulation was also shown to be effective in alleviating decreases in ROM due to muscle fatigue., Conclusions: This model will be useful for investigating the ability of rhythmic muscular electrical stimulation therapy to promote motor recovery, in addition to the efficacy of combining treatments with spinal cord regeneration therapy after spinal cord injuries.

Previous studies have revealed that cell therapy using bone marrow stromal cells (BMSCs) could promote motor functional recovery in animals with spinal cord injury (SCI). We describe here the development of cell biology technique and the experimental study of regeneration in SCI. The aim of this study was to investigate the potential for neurological recovery by transplantation neurospheres (NS) derived from BMSCs into thoracic SCI. Adult Fisher rats were used: 45 were subjected to complete thoracic SCI performed by the balloon compression method. BMSCs were cultured in vitro to obtain NS. Seven days after thoracic SCI, groups of 15 rats each received transplants of BMSCs-NS (group A), BMSCs (group B), or injection of medium only (group C) into the SCI lesion. Rats from each group were evaluated and compared longitudinally for motor function recovery. The spinal cords (SC) of injured rats were harvested at day 21 or day 42 and prepared for histological analysis. Five weeks after transplantation, many neuronal or axonal sproutings were observed and replaced by host cells in the SCI lesion of group A. Also, transplanted BMSCs-NS expressed neuronal lineage markers. Transplanted rats could walk with weight bearing and showed recovered motor evoked potentials (MEPs).

A recent study of a rat model treated with grafted collagen filament (CF) after spinal cord transection showed dramatic recovery of motor function but did not report on the acute-stage phenomenon. In the present study, we describe molecular and histological aspects of the axonal regeneration process during the acute stage following spinal cord transection. The spinal cord of 8-week-old rats was completely transected, and a scaffold of almost the same size as the resected portion was implanted in the gap. Changes in the mRNA expression of four neurotrophic factors [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, and glial cell-derived neurotrophic factor (GDNF)] were analyzed after 72 h. The expression of BDNF and NT-3 mRNA increased significantly in the CF-grafted group compared to the nongrafted group. Immunostaining for BDNF and NT-3 revealed that cells positive for these neurotrophic factors extended along the collagen filaments in the CF-grafted group. Similarly, astrocytes extended into the collagen filament scaffold together with the neurotrophic factors and partly across a border line. These findings indicate that collagen filament helps to reduce scar tissue, supports the expression of neurotrophic factors, and serves as a scaffold for the outgrowth of regenerating axons.

This study is nationwide retrospective multi-center study to investigate the incidence and characteristics of blunt cerebrovascular injury (BCVI) in elderly Japanese patients with traumatic cervical spine injuries (CSI) including spinal cord injury (SCI) without major bone injury. The study enrolled 1512 patients (average age: 75.8 ± 6.9 years; 1007 males, 505 females) from 33 nationwide institutions, and 391 (26%) of the participants had digital subtraction angiography and/or computed tomography angiography. Fifty-three patients were diagnosed as having BCVI by angiography. We assessed neurological evaluation, comorbidities and classification of CSI in the elderly patients with/without BCVI and collected 6-month follow-up data on treatment, complications, and patient outcome. We also statistically analyzed the relative risk (RR) and relationship between BCVI and other factors. Significant differences were identified between BCVI (+) (n = 53) and (–) (n = 1459) patients with American Spinal Injury Association Impairment Scale (ASIA) A, C, D, cervical fracture, C3-7 injury level (AO type F and/or C), cervical dislocation, spinal surgery for CSI, tetraplegia type of SCI, and/or head injury. Fifty-three (3.5%) elderly patients had CSI complicated by BCVI including 10 (19%) cases of Denver grade I, four (7%) of grade II, 1 (2%) of grade III, 29 (55%) of grade IV, and nine (17%) of grade V. Sixteen cases were treated by interventional radiology. Rates of mortality and brain infarction from BCVI were 0.13% and 0.40%, respectively. RR of BCVI was significantly higher in the elderly cervical injury patients with head injury, severe neurological deficit, ASIA A (RR: 4.33), cervical fracture at the C3-7 level (RR: 7.39), and cervical dislocation at the C1-6 level (RR: 3.06-7.18). In conclusion, 53 (3.5%) elderly patients were complicated with BCVI. BCVI more frequently complicated head injury, severe neurological deficit (ASIA A or tetraplegia), AO type F, and/or C fractures and cervical dislocation in these patients. Six patients (11%) suffered brain infarction and two patients died from BCVI. [ABSTRACT FROM AUTHOR]

Chronic spinal cord injury (SCI) is a devastating condition that results in major neurological deficits and social burden. It continues to be managed symptomatically, and no real therapeutic strategies have been devised for its treatment. Neural stem/neural progenitor cells (NSCs/NPCs) being used for the treatment of chronic SCI in experimental SCI models can not only replace the lost cells and remyelinate axons in the injury site but also support their growth and provide neuroprotective factors. Currently, several clinical studies using NSCs/NPCs are underway worldwide. NSCs/NPCs also have the potential to differentiate into all three neuroglial lineages to regenerate neural circuits, demyelinate denuded axons, and provide trophic support to endogenous cells. This article explains the challenging pathophysiology of chronic SCI and discusses key NSC/NPC-based techniques having the greatest potential for translation over the next decade. [ABSTRACT FROM AUTHOR]

Background: Rehabilitation facilitates the reorganization of residual/regenerated neural pathways and is key in improving motor function following spinal cord injury. Neuromuscular electrical stimulation (NMES) has been reported as being clinically effective. Although it can be used after the acute phase post-injury, the optimal stimulation conditions to improve motor function remain unclear. In this paper, we examined the effectiveness of NMES with alternating currents in the kilohertz (kHz) frequency in gait rhythm stimulation therapy.Methods: Tests were performed using 20 mature female Fischer rats. Incomplete spinal cord injuries (T9 level) were made with an IH impactor using a force of 150 kdyn, and NMES was administered for 3 days from the 7th day post-injury. The needle electrodes were inserted percutaneously near the motor point of each muscle in conscious rats, and each muscle on the left and right leg was stimulated for 15 min at two frequencies, 75 Hz and 8 kHz, to induce a gait rhythm. Motor function was evaluated using Basso, Beattie, Bresnahan (BBB) scores and three-dimensional (3D) gait analysis. Rats were divided into four groups (5 rats/group), including the NMES treatment 75-Hz group (iSCI-NMES 75 Hz), 8-kHz group (iSCI-NMES 8 kHz), injury control group (iSCI-NT), and normal group (Normal-CT), and were compared.Results: There was no significant difference in BBB scores among the three groups. In 3D gait analysis, compared with the injury control group, the 8-kHz group showed a significant improvement in synergistic movement of both hindlimbs.Conclusion: We suggest that kHz stimulation is effective in gait rhythm stimulation using NMES. [ABSTRACT FROM AUTHOR]

Cervical spinal cord injuries (cSCI) have devastating long-term consequences for patients' physical, social, and vocational wellbeing. Induced pluripotent stem cell-derived neural stem cell (iPS-NSC) transplants are an exciting therapeutic strategy to remyelinate denuded axons, replace neural circuits, and provide trophic support. However, the dense chondroitin sulfate proteoglycan (CSPG) scar in chronic injuries poses a significant challenge to effective cell migration and neurite outgrowth. Chondroitinase ABC (ChABC) is an enzyme capable of rapidly degrading CSPGs to enhance recovery. We investigated a novel combinatorial approach delivering intrathecal ChABC for 7 days followed by intraparenchymal murine iPS-NSC transplant in a clinically-relevant murine chronic cSCI model. We compared the (1) combinatorial treatment with (2) ChABC alone, (3) iPS-NSC transplant alone, (4) vehicle-treatment alone, and (5) sham injury (laminectomy alone). Behavioural assessments were completed weekly for 9 weeks post-transplant. We found that ChABC pretreatment dramatically reduced CSPG scarring and resulted in greater subsequent iPSC-NSC survival (7.8% vs 2.4%), particularly at the lesion epicenter. Combinatorial treatment also resulted in greater preservation of cholinergic neurons (ChAT +, NeuN + ; 7516 - 832) compared to iPS-NSC (4904 ± 1243) or ChABC (5890 - 552) treatments alone. Functionally, only animals receiving the combined therapy demonstrated consistent recovery of forelimb grip strength compared to vehicle-treated controls. This study provides key evidence for the synergistic effects of ChABC pre-treatment with iPSNSC transplant and opens a new avenue of research in developing an effective therapy for patients with cSCI. [ABSTRACT FROM AUTHOR]