Influence of the timing of surgery for cervical spinal cord injury without bone injury in the elderly: A retrospective multicenter study.

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.

Zinc deficiency impairs axonal regeneration and functional recovery after spinal cord injury by modulating macrophage polarization via NF-κB pathway.

Background: Spinal cord injury (SCI) is a devastating disease that results in permanent paralysis. Currently, there is no effective treatment for SCI, and it is important to identify factors that can provide therapeutic intervention during the course of the disease. Zinc, an essential trace element, has attracted attention as a regulator of inflammatory responses. In this study, we investigated the effect of zinc status on the SCI pathology and whether or not zinc could be a potential therapeutic target. Methods: We created experimental mouse models with three different serum zinc concentration by changing the zinc content of the diet. After inducing contusion injury to the spinal cord of three mouse models, we assessed inflammation, apoptosis, demyelination, axonal regeneration, and the number of nuclear translocations of NF-κB in macrophages by using qPCR and immunostaining. In addition, macrophages in the injured spinal cord of these mouse models were isolated by flow cytometry, and their intracellular zinc concentration level and gene expression were examined. Functional recovery was assessed using the open field motor score, a foot print analysis, and a grid walk test. Statistical analysis was performed using Wilcoxon rank-sum test and ANOVA with the Tukey-Kramer test. Results: In macrophages after SCI, zinc deficiency promoted nuclear translocation of NF-κB, polarization to pro-inflammatory like phenotype and expression of pro-inflammatory cytokines. The inflammatory response exacerbated by zinc deficiency led to worsening motor function by inducing more apoptosis of oligodendrocytes and demyelination and inhibiting axonal regeneration in the lesion site compared to the normal zinc condition. Furthermore, zinc supplementation after SCI attenuated these zinc-deficiency-induced series of responses and improved motor function. Conclusion: We demonstrated that zinc affected axonal regeneration and motor functional recovery after SCI by negatively regulating NF-κB activity and the subsequent inflammatory response in macrophages. Our findings suggest that zinc supplementation after SCI may be a novel therapeutic strategy for SCI.

Macrophages play a leading role in determining the direction of astrocytic migration in spinal cord injury via ADP-P2Y1R axis.

After spinal cord injury (SCI), inflammatory cells such as macrophages infiltrate the injured area, and astrocytes migrate, forming a glial scar around macrophages. The glial scar inhibits axonal regeneration, resulting in significant permanent disability. However, the mechanism through which glial scar-forming astrocytes migrate to the injury site has not been clarified. Here we show that migrating macrophages attract reactive astrocytes toward the center of the lesion after SCI. Chimeric mice with bone marrow lacking IRF8, which controls macrophage centripetal migration after SCI, showed widely scattered macrophages in the injured spinal cord with the formation of a huge glial scar around the macrophages. To determine whether astrocytes or macrophages play a leading role in determining the directions of migration, we generated chimeric mice with reactive astrocyte-specific Socs3-/- mice, which showed enhanced astrocyte migration, and bone marrow from IRF8-/- mice. In this mouse model, macrophages were widely scattered, and a huge glial scar was formed around the macrophages as in wild-type mice that were transplanted with IRF8-/- bone marrow. In addition, we revealed that macrophage-secreted ATP-derived ADP attracts astrocytes via the P2Y1 receptor. Our findings revealed a mechanism through which migrating macrophages attract astrocytes and affect the pathophysiology and outcome after SCI.

Bone marrow-derived fibroblast migration via periostin causes irreversible arthrogenic contracture after joint immobilization.

Joint contracture causes distressing permanent mobility disorder due to trauma, arthritis, and aging, with no effective treatment available. A principal and irreversible cause of joint contracture has been regarded as the development of joint capsule fibrosis. However, the molecular mechanisms underlying contracture remain unclear. We established a mouse model of knee joint contracture, revealing that fibrosis in joint capsules causes irreversible contracture. RNA-sequencing of contracture capsules demonstrated a marked enrichment of the genes involved in the extracellular region, particularly periostin (Postn). Three-dimensional magnetic resonance imaging and immunohistological analysis of contracture patients revealed posterior joint capsule thickening with abundant type I collagen (Col1a2) and POSTN in humans. Col1a2-GFPTG ; Postn-/- mice and chimeric mice with Col1a2-GFPTG ; tdTomatoTG bone marrow showed fibrosis in joint capsules caused by bone marrow-derived fibroblasts, and POSTN promoted the migration of bone marrow-derived fibroblasts, contributing to fibrosis and contracture. Conversely, POSTN-neutralizing antibody attenuated contracture exacerbation. Our findings identified POSTN as a key inducer of fibroblast migration that exacerbates capsule fibrosis, providing a potential therapeutic strategy for joint contracture.

Characteristics of the cervical spine and cervical cord injuries in older adults with cervical ossification of the posterior longitudinal ligament.

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.

Epidemiology of Cervical Fracture/Cervical Spinal Cord Injury and Changes in Surgical Treatment Modalities in Elderly Individuals During a 10-year Period: A Nationwide Multicenter Study in Japan.

STUDY DESIGN: Retrospective multicenter study. OBJECTIVES: To investigate changes over a 10-years period in the profile of cervical spine and spinal cord injuries among the elderly in Japan. METHODS: The current multicenter study was a retrospective analysis of inpatients aged ≥65 years, suffering cervical fracture (CF) and/or cervical spinal cord injury (CSCI). We analyzed 1413 patients' epidemiology (from 2010 to 2019). Moreover, 727 patients who underwent surgical treatment were analyzed in 2 groups: the early (2010-2014) and late period (2015-2019). RESULTS: Both the number of patients and number of surgical patients showed a significant increasing trend (P < .001), while the mean age, the distribution of injury levels and paralysis severity, and the proportion of surgical indications remained the same. The number of surgical patients doubled from 228 to 499 from the early to late periods. Posterior surgery was the most common approach (90.4%), instrumentation surgery with screws increased significantly, and the range of fusion was significantly longer in the late period (2.1 vs 2.7 levels, P = .001). Significantly worsening neurological symptoms were recorded in the late period (1.3% vs 5.8%, P = .006), with C5 palsy being the major one. Otherwise, perioperative, major, and other complications, including mortality, did not differ significantly in incidence. CONCLUSIONS: Both the number of elderly CF and/or CSCI patients and number of patients undergoing surgery increased dramatically over the decade without any change in profile. Instrumentation surgeries with screws increased, without an increase in systemic complications.

Risk Factors for Early Mortality in Older Patients with Traumatic Cervical Spine Injuries-A Multicenter Retrospective Study of 1512 Cases.

For older patients with decreased reserve function, traumatic cervical spine injuries frequently lead to early mortality. However, the prognostic factors for early mortality remain unclear. This study included patients aged ≥65 years and hospitalized for treatment of traumatic cervical spine injuries in 78 hospitals between 2010 and 2020. Early mortality was defined as death within 90 days after injury. We evaluated the relationship between early mortality and the following factors: age, sex, body mass index, history of drinking and smoking, injury mechanisms, presence of a cervical spine fracture and dislocation, cervical ossification of the posterior longitudinal ligament, diffuse idiopathic skeletal hyperostosis, American Spinal Injury Association Impairment Scale, concomitant injury, pre-existing comorbidities, steroid administration, and treatment plan. Overall, 1512 patients (mean age, 75.8 ± 6.9 years) were included in the study. The early mortality rate was 4.0%. Multivariate analysis identified older age (OR = 1.1, p < 0.001), male sex (OR = 3.7, p = 0.009), cervical spine fracture (OR = 4.2, p < 0.001), complete motor paralysis (OR = 8.4, p < 0.001), and chronic kidney disease (OR = 5.3, p < 0.001) as risk factors for early mortality. Older age, male sex, cervical spine fracture, complete motor paralysis, and chronic kidney disease are prognostic factors for early mortality in older patients with traumatic cervical spine injuries.

Is Blood Loss Greater in Elderly Patients under Antiplatelet or Anticoagulant Medication for Cervical Spine Injury Surgery? A Japanese Multicenter Survey.

Introduction: In elderly patients with cervical spinal cord injury, comorbidities such as cardiovascular and cerebrovascular diseases are common, with frequent administration of antiplatelet/anticoagulant (APAC) drugs. Such patients may bleed easily or unexpectedly during surgery despite prior withdrawal of APAC medication. Few reports have examined the precise relationship between intraoperative blood loss and history of APAC use regarding surgery for cervical spine injury in the elderly. The present multicenter database survey aimed to answer the question of whether the use of APAC drugs affected the amount of intraoperative blood loss in elderly patients with cervical spinal cord trauma. Methods: The case histories of 1512 patients with cervical spine injury at 33 institutes were retrospectively reviewed. After excluding cases without spinal surgery or known blood loss volume, 797 patients were enrolled. Blood volume loss was the outcome of interest. We calculated propensity scores using the inverse probability of treatment weighting (IPTW) method. As an alternative sensitivity analysis, linear mixed model analyses were conducted as well. Results: Of the 776 patients (mean age: 75.1±6.4 years) eligible for IPTW calculation, 157 (20.2%) were taking APAC medications before the injury. After weighting, mean estimated blood loss was 204 mL for non-APAC patients and 215 mL for APAC patients. APAC use in elderly patients was not significantly associated with surgical blood loss according to the IPTW method with propensity scoring or linear mixed model analyses. Thus, it appeared possible to perform surgery expecting comparable blood loss in APAC and non-APAC cases. Conclusions: This multicenter study revealed no significant increase in surgical blood loss in elderly patients with cervical trauma taking APAC drugs. Surgeons may be able to prioritize patient background, complications, and preexisting conditions over APAC use before injury when examining the surgical indications for cervical spine trauma in the elderly.

Zinc chelator treatment in crush syndrome model mice attenuates ischemia-reperfusion-induced muscle injury due to suppressing of neutrophil infiltration.

In crush syndrome, massive muscle breakdown resulting from ischemia-reperfusion muscle injury can be a life-threatening condition that requires urgent treatment. Blood reperfusion into the ischemic muscle triggers an immediate inflammatory response, and neutrophils are the first to infiltrate and exacerbate the muscle damage. Since free zinc ion play a critical role in the immune system and the function of neutrophils is impaired by zinc depletion, we hypothesized that the administration of a zinc chelator would be effective for suppressing the inflammatory reaction at the site of ischemia-reperfusion injury and for improving of the pathology of crush syndrome. A crush syndrome model was created by using a rubber tourniquet to compress the bilateral hind limbs of mice at 8 weeks. A zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) was administered immediately after reperfusion in order to assess the anti-inflammatory effect of the chelator for neutrophils. Histopathological evaluation showed significantly less muscle breakdown and fewer neutrophil infiltration in TPEN administration group compared with control group. In addition, the expression levels of inflammatory cytokine and chemokine such as IL-6, TNFα, CXCL1, CXCL2, CXCR2, CCL2 in ischemia-reperfusion injured muscle were significantly suppressed with TPEN treatment. Less dilatation of renal tubules in histological evaluation in renal tissue and significantly better survival rate were demonstrated in TPEN treatment for ischemia-reperfusion injury in crush syndrome. The findings of our study suggest that zinc chelators contributed to the resolution of exacerbation of the inflammatory response and attenuation of muscle breakdown in the acute phase after crush syndrome. In addition, our strategy of attenuation of the acute inflammatory reaction by zinc chelators may provide a promising therapeutic strategy not only for crush syndrome, but also for other diseases driven by inflammatory reactions.

Factors Affecting the Waiting Time from Injury to Surgery in Elderly Patients with a Cervical Spine Injury: A Japanese Multicenter Survey.

OBJECTIVE: The management of cervical spine injuries in the elderly is often complicated by the presence of multiple medical comorbidities, and it is not uncommon for preoperative testing to reveal other conditions that require the postponement of surgery. However, the factors that affect the waiting time from injury to surgery have not been clarified. The purpose of this multicenter database study was to analyze the clinical features and identify the factors affecting the number of days waited between injury and surgery in elderly patients with a cervical spine injury. METHODS: We retrospectively reviewed the case histories of 1512 Japanese patients with a cervical spinal injury, who were seen at 33 institutions. After excluding patients who were not initially receiving a surgery for cervical spinal injury, 694 patients were ultimately analyzed. Based on a multivariate mixed model, we determined the factors related to the number of days from injury to surgery. RESULTS: The mean time from injury to surgery was 12.3 days. Multivariate analysis revealed delays of 10.7 days for a renal disorder, 7.3 days for anticoagulant use, and 15.2 days for non-surgical thoracolumbar fracture as factors prolonging wait time. In contrast, a C3 or lower spine injury was significantly associated with a shortening of 9.5 days to surgery. CONCLUSIONS: This multicenter database study identified several factors influencing the time between injury and cervical spine surgery in elderly patients. While renal impairment, anticoagulant use, and non-surgical thoracolumbar fracture may increase the number of days to surgery, trauma to C3 or lower may expedite surgical treatment.

A multicenter study of 1-year mortality and walking capacity after spinal fusion surgery for cervical fracture in elderly patients.

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.

Does surgery improve neurological outcomes in older individuals with cervical spinal cord injury without bone injury? A multicenter study.

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.

Epidural Fat Tissue Is More Effective for Scar Prevention Than Conventional Subcutaneous Fat Grafting After Laminectomy in a Mouse Model.

STUDY DESIGN: Basic science study. OBJECTIVE: The aim of this study was to examine whether epidural fat tissue (EFT) transplantation can prevent epidural adhesion after laminectomy more efficiently than subcutaneous fat tissue (SFT) transplantation. SUMMARY OF BACKGROUND DATA: Epidural adhesion is almost inevitable after laminectomy. Although many materials have been used to prevent adhesion, none has been widely accepted. As EFT is an ectopic fat tissue located on the dura mater and there is no adhesion between EFT and the dura mater, we focused on the efficacy of EFT for adhesion prevention. METHODS: We examined the differences in histology and gene expression between EFT and SFT of mice. We performed laminectomy at the 10th thoracic level and immediately transplanted EFT or SFT to the dura mater in mice. At 6 weeks after transplantation, we performed histological and gene expression analyses and evaluated the adhesion tenacity. In addition, we examined the characteristic differences between human EFT and SFT. RESULTS: The adipocytes of EFT were significantly smaller than those of SFT in mice and humans. The gene expression of inflammatory cytokine and fibrosis-related factors was significantly higher in SFT than in EFT. At 6 weeks after transplantation, the percentage of the remaining fat area over the dura mater was significantly greater in the EFT group than in SFT group, and the adhesion tenacity score was significantly lower in the EFT group than that in the SFT group. An RNA sequencing analysis revealed 1921 differentially expressed genes (DEGs) between human EFT and SFT, and a Gene Ontology term associated with the inflammatory response was most highly enriched in SFT. CONCLUSION: EFT has different molecular and histological profiles from SFT and EFT grafting is more effective for epidural adhesion prevention than conventional SFT transplantation after laminectomy in a mouse model.Level of Evidence: N/A.

Management of Airway Obstruction due to Diffuse Idiopathic Skeletal Hyperostosis in the Cervical Spine: A Case Report and Literature Review.

Diffuse idiopathic skeletal hyperostosis (DISH) is a relatively common progressive noninflammatory entheses disease. Patients are often asymptomatic or are undiagnosed due to minor chronic symptoms. We herein report a rare case in which the primary symptom was sudden-onset upper airway obstruction due to exuberant osteophytosis in the cervical spine. Treatment was successful with careful airway management and surgical osteophyectomy. Most DISH cases in the literature with airway obstruction have been managed with tracheotomy. However, the safety and necessity of this approach remain questionable. We herein discuss the possibility of conservative management as a choice of airway control. Airway obstruction due to DISH may be underrecognized. This highlights the importance of including DISH in the differential diagnosis of airway obstruction. In addition, a detailed evaluation and personalized care for each individual case is essential.