Inhibition of the Nogo-pathway in experimental spinal cord injury: a meta-analysis of 76 experimental treatments.

Recovery after spinal cord injury (SCI) may be propagated by plasticity-enhancing treatments. The myelin-associated nerve outgrowth inhibitor Nogo-A (Reticulon 4, RTN4) pathway has been shown to restrict neuroaxonal plasticity in experimental SCI models. Early randomized controlled trials are underway to investigate the effect of Nogo-A/Nogo-Receptor (NgR1) pathway blockers. This systematic review and meta-analysis of therapeutic approaches blocking the Nogo-A pathway interrogated the efficacy of functional locomotor recovery after experimental SCI according to a pre-registered study protocol. A total of 51 manuscripts reporting 76 experiments in 1572 animals were identified for meta-analysis. Overall, a neurobehavioral improvement by 18.9% (95% CI 14.5-23.2) was observed. Subgroup analysis (40 experiments, N = 890) revealed SCI-modelling factors associated with outcome variability. Lack of reported randomization and smaller group sizes were associated with larger effect sizes. Delayed treatment start was associated with lower effect sizes. Trim and Fill assessment as well as Egger regression suggested the presence of publication bias. Factoring in theoretically missing studies resulted in a reduced effect size [8.8% (95% CI 2.6-14.9)]. The available data indicates that inhibition of the Nogo-A/NgR1pathway alters functional recovery after SCI in animal studies although substantial differences appear for the applied injury mechanisms and other study details. Mirroring other SCI interventions assessed earlier we identify similar factors associated with outcome heterogeneity.

Adverse Effect of Neurogenic, Infective, and Inflammatory Fever on Acutely Injured Human Spinal Cord.

This study aims to determine the effect of neurogenic, inflammatory, and infective fevers on acutely injured human spinal cord. In 86 patients with acute, severe traumatic spinal cord injuries (TSCIs; American Spinal Injury Association Impairment Scale (AIS), grades A-C) we monitored (starting within 72 h of injury, for up to 1 week) axillary temperature as well as injury site cord pressure, microdialysis (MD), and oxygen. High fever (temperature ≥38°C) was classified as neurogenic, infective, or inflammatory. The effect of these three fever types on injury-site physiology, metabolism, and inflammation was studied by analyzing 2864 h of intraspinal pressure (ISP), 1887 h of MD, and 840 h of tissue oxygen data. High fever occurred in 76.7% of the patients. The data show that temperature was higher in neurogenic than non-neurogenic fever. Neurogenic fever only occurred with injuries rostral to vertebral level T4. Compared with normothermia, fever was associated with reduced tissue glucose (all fevers), increased tissue lactate to pyruvate ratio (all fevers), reduced tissue oxygen (neurogenic + infective fevers), and elevated levels of pro-inflammatory cytokines/chemokines (infective fever). Spinal cord metabolic derangement preceded the onset of infective but not neurogenic or inflammatory fever. By considering five clinical characteristics (level of injury, axillary temperature, leukocyte count, C-reactive protein [CRP], and serum procalcitonin [PCT]), it was possible to confidently distinguish neurogenic from non-neurogenic high fever in 59.3% of cases. We conclude that neurogenic, infective, and inflammatory fevers occur commonly after acute, severe TSCI and are detrimental to the injured spinal cord with infective fever being the most injurious. Further studies are required to determine whether treating fever improves outcome. Accurately diagnosing neurogenic fever, as described, may reduce unnecessary septic screens and overuse of antibiotics in these patients.

The spinal cord injury-induced immune deficiency syndrome: results of the SCIentinel study.

Infections are prevalent after spinal cord injury (SCI), constitute the main cause of death and are a rehabilitation confounder associated with impaired recovery. We hypothesize that SCI causes an acquired lesion-dependent (neurogenic) immune suppression as an underlying mechanism to facilitate infections. The international prospective multicentre cohort study (SCIentinel; protocol registration DRKS00000122; n = 111 patients) was designed to distinguish neurogenic from general trauma-related effects on the immune system. Therefore, SCI patient groups differing by neurological level, i.e. high SCI [thoracic (Th)4 or higher]; low SCI (Th5 or lower) and severity (complete SCI; incomplete SCI), were compared with a reference group of vertebral fracture (VF) patients without SCI. The primary outcome was quantitative monocytic Human Leukocyte Antigen-DR expression (mHLA-DR, synonym MHC II), a validated marker for immune suppression in critically ill patients associated with infection susceptibility. mHLA-DR was assessed from Day 1 to 10 weeks after injury by applying standardized flow cytometry procedures. Secondary outcomes were leucocyte subpopulation counts, serum immunoglobulin levels and clinically defined infections. Linear mixed models with multiple imputation were applied to evaluate group differences of logarithmic-transformed parameters. Mean quantitative mHLA-DR [ln (antibodies/cell)] levels at the primary end point 84 h after injury indicated an immune suppressive state below the normative values of 9.62 in all groups, which further differed in its dimension by neurological level: high SCI [8.95 (98.3% confidence interval, CI: 8.63; 9.26), n = 41], low SCI [9.05 (98.3% CI: 8.73; 9.36), n = 29], and VF without SCI [9.25 (98.3% CI: 8.97; 9.53), n = 41, P = 0.003]. Post hoc analysis accounting for SCI severity revealed the strongest mHLA-DR decrease [8.79 (95% CI: 8.50; 9.08)] in the complete, high SCI group, further demonstrating delayed mHLA-DR recovery [9.08 (95% CI: 8.82; 9.38)] and showing a difference from the VF controls of -0.43 (95% CI: -0.66; -0.20) at 14 days. Complete, high SCI patients also revealed constantly lower serum immunoglobulin G [-0.27 (95% CI: -0.45; -0.10)] and immunoglobulin A [-0.25 (95% CI: -0.49; -0.01)] levels [ln (g/l × 1000)] up to 10 weeks after injury. Low mHLA-DR levels in the range of borderline immunoparalysis (below 9.21) were positively associated with the occurrence and earlier onset of infections, which is consistent with results from studies on stroke or major surgery. Spinal cord injured patients can acquire a secondary, neurogenic immune deficiency syndrome characterized by reduced mHLA-DR expression and relative hypogammaglobulinaemia (combined cellular and humoral immune deficiency). mHLA-DR expression provides a basis to stratify infection-risk in patients with SCI.

Lesional Antibody Synthesis and Complement Deposition Associate With De Novo Antineuronal Antibody Synthesis After Spinal Cord Injury.

BACKGROUND AND OBJECTIVES: Spinal cord injury (SCI) disrupts the fine-balanced interaction between the CNS and immune system and can cause maladaptive aberrant immune responses. The study examines emerging autoantibody synthesis after SCI with binding to conformational spinal cord epitopes and surface peptides located on the intact neuronal membrane. METHODS: This is a prospective longitudinal cohort study conducted in acute care and inpatient rehabilitation centers in conjunction with a neuropathologic case-control study in archival tissue samples ranging from acute injury (baseline) to several months thereafter (follow-up). In the cohort study, serum autoantibody binding was examined in a blinded manner using tissue-based assays (TBAs) and dorsal root ganglia (DRG) neuronal cultures. Groups with traumatic motor complete SCI vs motor incomplete SCI vs isolated vertebral fracture without SCI (controls) were compared. In the neuropathologic study, B cell infiltration and antibody synthesis at the spinal lesion site were examined by comparing SCI with neuropathologically unaltered cord tissue. In addition, the CSF in an individual patient was explored. RESULTS: Emerging autoantibody binding in both TBA and DRG assessments was restricted to an SCI patient subpopulation only (16%, 9/55 sera) while being absent in vertebral fracture controls (0%, 0/19 sera). Autoantibody binding to the spinal cord characteristically detected the substantia gelatinosa, a less-myelinated region of high synaptic density involved in sensory-motor integration and pain processing. Autoantibody binding was most frequent after motor complete SCI (grade American Spinal Injury Association impairment scale A/B, 22%, 8/37 sera) and was associated with neuropathic pain medication. In conjunction, the neuropathologic study demonstrated lesional spinal infiltration of B cells (CD20, CD79a) in 27% (6/22) of patients with SCI, the presence of plasma cells (CD138) in 9% (2/22). IgG and IgM antibody syntheses colocalized to areas of activated complement (C9neo) deposition. Longitudinal CSF analysis of an additional single patient demonstrated de novo (IgM) intrathecal antibody synthesis emerging with late reopening of the blood-spinal cord barrier. DISCUSSION: This study provides immunologic, neurobiological, and neuropathologic proof-of-principle for an antibody-mediated autoimmunity response emerging approximately 3 weeks after SCI in a patient subpopulation with a high demand of neuropathic pain medication. Emerging autoimmunity directed against specific spinal cord and neuronal epitopes suggests the existence of paratraumatic CNS autoimmune syndromes.

Effect of body mass index on survival after spinal cord injury.

Introduction: Increased mortality after acute and chronic spinal cord injury (SCI) remains a challenge and mandates a better understanding of the factors contributing to survival in these patients. This study investigated whether body mass index (BMI) measured after acute traumatic SCI is associated with a change in mortality. Methods: A prospective longitudinal cohort study was conducted with 742 patients who were admitted to the Acute Spine Unit of the Vancouver General Hospital between 2004 and 2016 with a traumatic SCI. An investigation of the association between BMI on admission and long-term mortality was conducted using classification and regression tree (CART) and generalized additive models (spline curves) from acute care up to 7.7 years after SCI (chronic phase). Multivariable models were adjusted for (i) demographic factors (e.g., age, sex, and Charlson Comorbidity Index) and (ii) injury characteristics (e.g., neurological level and severity and Injury Severity Score). Results: After the exclusion of incomplete datasets (n = 602), 643 patients were analyzed, of whom 102 (18.5%) died during a period up to 7.7 years after SCI. CART identified three distinct mortality risk groups: (i) BMI: > 30.5 kg/m2, (ii) 17.5-30.5 kg/m2, and (iii) < 17.5 kg/m2. Mortality was lowest in the high BMI group (BMI > 30.5 kg/m2), followed by the middle-weight group (17.5-30.5 kg/m2), and was highest in the underweight group (BMI < 17.5 kg/m2). High BMI had a mild protective effect against mortality after SCI (hazard ratio 0.28, 95% CI: 0.09-0.88, p = 0.029), concordant with a modest "obesity paradox". Moreover, being underweight at admission was a significant risk factor for mortality up to 7.7 years after SCI (hazard ratio 5.5, 95% CI: 2.34-13.17, p < 0.001). Discussion: Mortality risk (1 month to 7.7 years after SCI) was associated with differences in BMI at admission. Further research is needed to better understand the underlying mechanisms. Given an established association of BMI with metabolic determinants, these results may suggest unknown neuro-metabolic pathways that are crucial for patient survival.

Baseline predictors of in-hospital mortality after acute traumatic spinal cord injury: data from a level I trauma center.

Comorbidity scores are important predictors of in-hospital mortality after traumatic spinal cord injury (tSCI), but the impact of specific pre-existing diseases is unknown. This retrospective cohort study aims at identifying relevant comorbidities and explores the influence of end-of-life decisions. In-hospital mortality of all patients admitted to the study center after acute tSCI from 2011 to 2017 was assessed. A conditional inference tree analysis including baseline data, injury characteristics, and Charlson Comorbidity Index items was used to identify crucial predictors. End-of-life decisions were recorded. Three-hundred-twenty-one patients were consecutively enrolled. The median length of stay was 95.7 days (IQR 56.8-156.0). During inpatient care, 20 patients (6.2%) died. These patients were older (median: 79.0 (IQR 74.7-83.2) vs. 55.5 (IQR 41.4-72.3) years) and had a higher Charlson Comorbidity Index score (median: 4.0 (IQR 1.75-5.50) vs. 0.0 (IQR 0.00-1.00)) compared to survivors. Pre-existing kidney or liver disease were identified as relevant predictors of in-hospital mortality. End-of-life decisions were observed in 14 (70.0%) cases. The identified impairment of kidney and liver, important for drug metabolism and elimination, points to the need of careful decisions on pharmaceutical treatment regimens after tSCI. Appropriate reporting of end-of-life decisions is required for upcoming studies.

Spinal infection with intraspinal abscess or empyema and acute myelopathy: comparative analysis of diagnostics, therapy, complications and outcome in primary care.

INTRODUCTION: This study on pyogenic spinal infections with intraspinal epidural involvement (PSI +) compared the outcome of patients with spinal cord injury (SCI) to those without (noSCI) taking diagnostic algorithm, therapy, and complications into account. METHODS: Patients were enrolled in an ambispective study (2012-2017). Diagnostic and therapeutic algorithms, complications, and neurological outcome were analyzed descriptively. Survival was analyzed applying Kaplan-Meier method and Cox regression. RESULTS: In total, 134 patients with a median (IQR) age of 72 (61-79) years were analyzed. Baseline characteristics were similar between the SCI (n = 55) and noSCI (n = 79). A higher percentage of endocarditis (9% vs. 0%; p = 0.03) was detected in the noSCI group. The majority (81%) received combinatorial therapy including spinal surgery and antibiotic treatment. The surgery complication rate was 16%. At discharge, improvement in neurologic function was present in 27% of the SCI patients. Length of stay, duration of ventilation and the burden of disease-associated complications were significantly higher in the SCI group (e.g., urinary tract infection, pressure ulcers). Lethality risk factors were age (HR 1.09, 95% CI 1.02-1.16, p = 0.014), and empyema/abscess extension (≥ 3 infected spinal segments, HR 4.72, 95% CI 1.57-14.20, p = 0.006), dominating over additional effects of Charlson comorbidity index, SCI, and type of treatment. The overall lethality rate was 11%. CONCLUSION: PSI + are associated with higher in-hospital mortality, particularly when multiple spinal segments are involved. However, survival is similar with (SCI) or without myelopathy (noSCI). If SCI develops, the rate of disease complications is higher and early specialized SCI care might be substantial to reduce complication rates.

The Effect of Early Infection on the Rate of Volitional Voiding after Spinal Cord Injury: A Potential Modifiable Risk Factor for Bladder Outcomes.

PURPOSE: Recently, it has been observed that early infections after spinal cord injury (SCI) are associated with decreased long-term motor and sensory recovery. We investigate the effects of early infection after SCI on long-term bladder function. MATERIALS AND METHODS: We assessed data for the years 1995 to 2006 using the National Spinal Cord Injury Database. Postoperative wound infections and pneumonia were used to classify infections during the acute inpatient and rehabilitation periods. The effect of early infections on volitional voiding status at 1-year followup was assessed. Age, gender and neurological status at rehabilitation discharge (level of injury, American Spinal Injury Association Impairment Scale [AIS] and bilateral lower extremity motor scores) were included in multivariate logistic regression modeling to control for confounding. RESULTS: Of the 3,561 persons studied, 1,233 (34.6%) had an early infection. Those with an infection during early recovery were less likely to void than their noninfected counterparts if in the AIS A (0.3% vs 1.9%, p=0.010), AIS B (3.8% vs 10.5%, p=0.018) and AIS C (29.1% vs 37.3%, p=0.071) classification, while those with less complete injuries (AIS D) did not appear to be affected (62.6% vs 65.4%, p=0.456). Similar findings were found when stratifying by lower extremity motor scores and persisted on multivariate analysis, where early infection decreased the odds of volitional voiding at 1-year followup (OR=0.79, p=0.042). CONCLUSIONS: Infections during the early recovery period may modify volitional voiding at 1-year followup by 20% or more. Future investigations to confirm our findings and potentially evaluate mitigation strategies are warranted.

Association of age with the timing of acute spine surgery-effects on neurological outcome after traumatic spinal cord injury.

PURPOSE: To investigate the association of age with delay in spine surgery and the effects on neurological outcome after traumatic spinal cord injury (SCI). METHODS: Ambispective cohort study (2011-2017) in n = 213 patients consecutively enrolled in a Level I trauma center with SCI care in a metropolitan region in Germany. Age-related differences in the injury to surgery interval and conditions associated with its delay (> 12 h after SCI) were explored using age categories or continuous variables and natural cubic splines. Effects of delayed surgery or age with outcome were analyzed using multiple logistic regression. RESULTS: The median age of the study population was 58.8 years (42.0-74.6 IQR). Older age (≥ 75y) was associated with a prolonged injury to surgery interval of 22.8 h (7.2-121.3) compared to 6.6 h (4.4-47.9) in younger patients (≤ 44y). Main reasons for delayed surgery in older individuals were secondary referrals and multimorbidity. Shorter time span to surgery (≤ 12 h) was associated with higher rates of ASIA impairment scale (AIS) conversion (OR 4.22, 95%CI 1.85-9.65), as mirrored by adjusted spline curves (< 20 h 20-25%, 20-60 h 10-20%, > 60 h < 10% probability of AIS conversion). In incomplete SCI, the probability of AIS conversion was lower in older patients [e.g., OR 0.09 (0.02-0.44) for'45-59y' vs.' ≤ 44y'], as confirmed by spline curves (< 40y 20-80%, ≥ 40y 5-20% probability). CONCLUSION: Older patient age complexifies surgical SCI care and research. Tackling secondary referral to Level I trauma centers and delayed spine surgery imposes as tangible opportunity to improve the outcome of older SCI patients.

Cervical Spine Injuries with Acute Traumatic Spinal Cord Injury: Spinal Surgery Adverse Events and Their Association with Neurological and Functional Outcome.

STUDY DESIGN: Monocenter case-control study. OBJECTIVE: Effects of spinal surgical adverse events (SSAE) on clinical and functional outcome, length of stay, and treatment costs after traumatic cervical spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: Traumatic SCI is a challenge for primary care centers because of the emergency setting and complex injury patterns. SSAE rates of up to 15% are reported for spine fractures without SCI. Little is known about SSAE after traumatic SCI and their outcome relevance. METHODS: Acute traumatic cervical SCI patients were enrolled from 2011 to 2017. Cases with and without SSAE were compared regarding neurological recovery, functional outcome, secondary complications, mortality, length of stay, and treatment costs. Adjusted logistic regression and generalized estimating equation models were calculated for the endpoints ASIA impairment scale (AIS)-conversion and dysphagia. All analyses were run in the total and in a propensity score matched sample. RESULTS: At least one SSAE occurred in 37 of 165 patients (22.4%). Mechanical instability and insufficient spinal decompression were the most frequent SSAE with 13 (7.9%) or 11 (6.7%) cases, respectively. The regression models adjusted for demographic, injury, and surgery characteristics demonstrated a reduced probability for AIS-conversion related to SSAE (OR [95% CI] 0.14 [0.03-0.74]) and additionally to single-sided ventral or dorsal surgical approach (0.12 [0.02-0.69]) in the matched sample. Furthermore, SSAE were associated with higher risk for dysphagia in the matched (4.77 [1.31-17.38]) and the total sample (5.96 [2.07-17.18]). Primary care costs were higher in cases with SSAE (median (interquartile range) 97,300 [78,200-112,300]) EUR compared with cases without SSAE (52,300 [26,700-91,200]) EUR. CONCLUSION: SSAE are an important risk factor after acute traumatic cervical SCI with impact on neurological recovery, functional outcome, and healthcare costs. Reducing SSAE is a viable means to protect the limited intrinsic capacity for recovery from SCI.Level of Evidence: 4.

Peripheral white blood cell responses as emerging biomarkers for patient stratification and prognosis in acute spinal cord injury.

PURPOSE OF REVIEW: To date, prognostication of patients after acute traumatic spinal cord injury (SCI) mostly relies on the neurological assessment of residual function attributed to lesion characteristics. With emerging treatment candidates awaiting to be tested in early clinical trials, there is a need for wholistic high-yield prognostic biomarkers that integrate both neurogenic and nonneurogenic SCI pathophysiology as well as premorbid patient characteristics. RECENT FINDINGS: It is becoming clearer that effective prognostication after acute SCI would benefit from integrating an assessment of pathophysiological changes on a systemic level, and with that, extend from a lesion-centric approach. Immunological markers mirror tissue injury as well as host immune function and are easily accessible through routine blood sampling. New studies have highlighted the value of circulating white blood cells, neutrophils and lymphocytes in particular, as prognostic systemic indicators of SCI severity and outcomes. SUMMARY: We survey recent advances in methods and approaches that may allow for a more refined diagnosis and better prognostication after acute SCI, discuss how these may help deepen our understanding of SCI pathophysiology, and be of use in clinical trials.

Prognostic value of early leukocyte fluctuations for recovery from traumatic spinal cord injury.

BACKGROUND: Acute traumatic spinal cord injury (SCI) induces a systemic immune response involving circulating white blood cells (WBCs). How this response is influenced by overall trauma severity, the neurological level of injury and/or correlates with patient outcomes is poorly understood. The objective of this study was to identify relationships between early changes in circulating WBCs, injury characteristics and long-term patient outcomes in individuals with traumatic SCI. METHODS: We retrospectively analysed data from 161 SCI patients admitted to Brisbane's Princess Alexandra Hospital (exploration cohort). Logistic regression models in conjunction with receiver operating characteristic (ROC) analyses were used to assess the strength of specific links between the WBC response, respiratory infection incidence and neurological outcomes (American Spinal Injury Association Impairment Scale (AIS) grade conversion). An independent validation cohort from the Trauma Hospital Berlin, Germany (n = 49) was then probed to assess the robustness of effects and disentangle centre effects. RESULTS: We find that the extent of acute neutrophilia in human SCI patients is positively correlated with New Injury Severity Scores but inversely with the neurological outcome (AIS grade). Multivariate analysis demonstrated that acute SCI-induced neutrophilia is an independent predictor of AIS grade conversion failure, with an odds ratio (OR) of 4.16 and ROC area under curve (AUC) of 0.82 (P < 0.0001). SCI-induced lymphopenia was separately identified as an independent predictor of better recovery (OR = 24.15; ROC AUC = 0.85, P < 0.0001). Acute neutrophilia and increased neutrophil-lymphocyte ratios were otherwise significantly associated with respiratory infection presentation in both patient cohorts. CONCLUSIONS: Our findings demonstrate the prognostic value of modelling early circulating neutrophil and lymphocyte counts with patient characteristics for predicting the longer term recovery after SCI.

The neuroanatomical-functional paradox in spinal cord injury.

Although lesion size is widely considered to be the most reliable predictor of outcome after CNS injury, lesions of comparable size can produce vastly different magnitudes of functional impairment and subsequent recovery. This neuroanatomical-functional paradox is likely to contribute to the many failed attempts to independently replicate findings from animal models of neurotrauma. In humans, the analogous clinical-radiological paradox could explain why individuals with similar injuries can respond differently to rehabilitation. We describe the neuroanatomical-functional paradox in the context of traumatic spinal cord injury (SCI) and discuss the underlying mechanisms of the paradox, including the concepts of lesion-affected and recovery-related networks. We also consider the various secondary complications that further limit the accuracy of outcome prediction in SCI and provide suggestions for how to increase the predictive, translational value of preclinical SCI models.

Association of timing of gabapentinoid use with motor recovery after spinal cord injury.

OBJECTIVE: To explore the hypothesis that earlier administration of acute gabapentinoids is beneficial to motor recovery after spinal cord injury in humans. METHODS: This is an observational study using a cohort from the European Multi-Centre Study about Spinal Cord Injury. Patient charts were reviewed to extract information regarding the administration and timing of gabapentinoid anticonvulsants. The primary outcome measure was motor scores, as measured by the International Standards for Neurological Classification of Spinal Cord Injury, collected longitudinally in the first year after injury. Sensory scores (light touch and pinprick) and functional measures (Spinal Cord Independence Measure) were secondary outcomes. Linear mixed effects regression models included a drug-by-time interaction to determine whether exposure to gabapentinoids altered recovery of muscle strength in the first year after injury. RESULTS: A total of 201 participants were included in the study and had a median age of 46 and baseline motor score of 50. Participants were mostly men (85%) with sensory and motor complete injuries (50%). Seventy individuals (35%) were administered gabapentinoids within the first 30 days after injury, and presented with similar demographics. In the longitudinal model, the administration of gabapentinoids within 30 days after injury was associated with improved motor recovery when compared to those who did not receive gabapentinoids during this time (3.69 additional motor points from 4 to 48 weeks after injury; p = 0.03). This effect size increased as administration occurred earlier after injury (i.e., a benefit of 4.68 points when administered within 5 days). CONCLUSIONS: This retrospective, observational study provided evidence of the beneficial effect of gabapentinoid anticonvulsants on motor recovery after spinal cord injury. More critically, it highlighted a potential time dependence, suggesting that earlier intervention is associated with better outcomes. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that gabapentinoids improve motor recovery for individuals with acute spinal cord injury.

Effects of local hypothermia-rewarming on physiology, metabolism and inflammation of acutely injured human spinal cord.

In five patients with acute, severe thoracic traumatic spinal cord injuries (TSCIs), American spinal injuries association Impairment Scale (AIS) grades A-C, we induced cord hypothermia (33 °C) then rewarming (37 °C). A pressure probe and a microdialysis catheter were placed intradurally at the injury site to monitor intraspinal pressure (ISP), spinal cord perfusion pressure (SCPP), tissue metabolism and inflammation. Cord hypothermia-rewarming, applied to awake patients, did not cause discomfort or neurological deterioration. Cooling did not affect cord physiology (ISP, SCPP), but markedly altered cord metabolism (increased glucose, lactate, lactate/pyruvate ratio (LPR), glutamate; decreased glycerol) and markedly reduced cord inflammation (reduced IL1ß, IL8, MCP, MIP1α, MIP1ß). Compared with pre-cooling baseline, rewarming was associated with significantly worse cord physiology (increased ICP, decreased SCPP), cord metabolism (increased lactate, LPR; decreased glucose, glycerol) and cord inflammation (increased IL1ß, IL8, IL4, IL10, MCP, MIP1α). The study was terminated because three patients developed delayed wound infections. At 18-months, two patients improved and three stayed the same. We conclude that, after TSCI, hypothermia is potentially beneficial by reducing cord inflammation, though after rewarming these benefits are lost due to increases in cord swelling, ischemia and inflammation. We thus urge caution when using hypothermia-rewarming therapeutically in TSCI.

Clinical decision-making on spinal cord injury-associated pneumonia: a nationwide survey in Germany.

STUDY DESIGN: Survey study. OBJECTIVES: Spinal cord injury (SCI)-associated pneumonia (SCI-AP) is associated with poor functional recovery and a major cause of death after SCI. Better tackling SCI-AP requires a common understanding on how SCI-AP is defined. This survey examines clinical algorithms relevant for diagnosis and treatment of SCI-AP. SETTING: All departments for SCI-care in Germany. METHODS: The clinical decision-making on SCI-AP and the utility of the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of 'clinically defined pneumonia' were assessed by means of a standardized questionnaire including eight case vignettes of suspected SCI-AP. The diagnostic decisions based on the case information were analysed using classification and regression trees (CART). RESULTS: The majority of responding departments were aware of the CDC-criteria (88%). In the clinical vignettes, 38-81% of the departments diagnosed SCI-AP in accordance with the CDC-criteria and 7-41% diagnosed SCI-AP in deviation from the CDC-criteria. The diagnostic agreement was not associated with the availability of standard operating procedures for SCI-AP management in the departments. CART analysis identified radiological findings, fever, and worsened gas exchange as most important for the decision on SCI-AP. Frequently requested supplementary diagnostics were microbiological analyses, C-reactive protein, and procalcitonin. For empirical antibiotic therapy, the departments used (acyl-)aminopenicillins/ß-lactamase inhibitors, cephalosporins, or combinations of (acyl-)aminopenicillins/ß-lactamase inhibitors with fluoroquinolones or carbapenems. CONCLUSIONS: This survey reveals a diagnostic ambiguity regarding SCI-AP despite the awareness of CDC-criteria and established SOPs. Heterogeneous clinical practice is encouraging the development of disease-specific guidelines for diagnosis and management of SCI-AP.

Outcome heterogeneity and bias in acute experimental spinal cord injury: A meta-analysis.

OBJECTIVE: To determine whether and to what degree bias and underestimated variability undermine the predictive value of preclinical research for clinical translation. METHODS: We investigated experimental spinal cord injury (SCI) studies for outcome heterogeneity and the impact of bias. Data from 549 preclinical SCI studies including 9,535 animals were analyzed with meta-regression to assess the effect of various study characteristics and the quality of neurologic recovery. RESULTS: Overall, the included interventions reported a neurobehavioral outcome improvement of 26.3% (95% confidence interval 24.3-28.4). Response to treatment was dependent on experimental modeling paradigms (neurobehavioral score, site of injury, and animal species). Applying multiple outcome measures was consistently associated with smaller effect sizes compared with studies applying only 1 outcome measure. More than half of the studies (51.2%) did not report blinded assessment, constituting a likely source of evaluation bias, with an overstated effect size of 7.2%. Assessment of publication bias, which extrapolates to identify likely missing data, suggested that between 2% and 41% of experiments remain unpublished. Inclusion of these theoretical missing studies suggested an overestimation of efficacy, reducing the effect sizes by between 0.9% and 14.3%. CONCLUSIONS: We provide empirical evidence of prevalent bias in the design and reporting of experimental SCI studies, resulting in overestimation of the effectiveness. Bias compromises the internal validity and jeopardizes the successful translation of SCI therapies from the bench to bedside.

The Incidence and Management of Moderate to Severe Head Injury.

BACKGROUND: The comprehensive expansion of the Trauma Register of the German Trauma Society (Deutsche Gesellschaft für Unfallchirurgie; TR-DGU) now enables, for the first time, studies on traumatic brain injury (TBI) with special attention to care processes, clinical course, and outcomes of treatment on discharge or transfer from the acute-care hospital. METHODS: Retrospective analysis of patients documented in the TR-DGU in the period 2013-2017 who had moderate to severe head injury as defined by the Abbreviated Injury Scale (AIS). RESULTS: In the period 2013-2017, 41 101 patients with moderate to severe TBI were treated in TR-DGU-associated hospitals in Germany (n = 605 hospitals), corresponding to 8220 cases per year and thus to a population-wide incidence of 10.1 cases per 100 000 persons per year. TBI was present as an isolated injury in 39.1% of cases. The mean age of the patients was 60 years (median; range 0-104 years), and the male-to-female ratio was 2:1. 97.5% of the patients had blunt trauma. Falls from a low height were the most common cause of TBI (38.7%). 43.6% of the patients were intubated before arriving at the hospital, and more than 95% underwent cranial tomographic imaging within 22 minutes of arrival (standard deviation [SD] = 17 minutes). 18.4% underwent an emergency neurosurgical procedure. The in-hospital mortality was 23.5%, corresponding to a population-wide mortality from TBI of 2.4 per 100 000 persons per year. More than half of the patients recovered well or with only mild disability; 14.9% had persistent severe disability or remained in a vegetative state. CONCLUSION: Putting these figures in the appropriate international context requires the acquisition of comparable data in multiple countries and is the main task of international TBI consortia.