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.

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.

International surveillance study in acute spinal cord injury confirms viability of multinational clinical trials.

BACKGROUND: The epidemiological international landscape of traumatic spinal cord injury (SCI) has evolved over the last decades along with given inherent differences in acute care and rehabilitation across countries and jurisdictions. However, to what extent these differences may influence neurological and functional recovery as well as the integrity of international trials is unclear. The latter also relates to historical clinical data that are exploited to inform clinical trial design and as potential comparative data. METHODS: Epidemiological and clinical data of individuals with traumatic and ischemic SCI enrolled in the European Multi-Center Study about Spinal Cord Injury (EMSCI) were analyzed. Mixed-effect models were employed to account for the longitudinal nature of the data, efficiently handle missing data, and adjust for covariates. The primary outcomes comprised demographics/injury characteristics and standard scores to quantify neurological (i.e., motor and sensory scores examined according to the International Standards for the Neurological Classification of Spinal Cord Injury) and functional recovery (walking function). We externally validated our findings leveraging data from a completed North American landmark clinical trial. RESULTS: A total of 4601 patients with acute SCI were included. Over the course of 20 years, the ratio of male to female patients remained stable at 3:1, while the distribution of age at injury significantly shifted from unimodal (2001/02) to bimodal distribution (2019). The proportional distribution of injury severities and levels remained stable with the largest percentages of motor complete injuries. Both, the rate and pattern of neurological and functional recovery, remained unchanged throughout the surveillance period despite the increasing age at injury. The findings related to recovery profiles were confirmed by an external validation cohort (n=791). Lastly, we built an open-access and online surveillance platform ("Neurosurveillance") to interactively exploit the study results and beyond. CONCLUSIONS: Despite some epidemiological changes and considerable advances in clinical management and rehabilitation, the neurological and functional recovery following SCI has remained stable over the last two decades. Our study, including a newly created open-access and online surveillance tool, constitutes an unparalleled resource to inform clinical practice and implementation of forthcoming clinical trials targeting neural repair and plasticity in acute spinal cord injury.

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.

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.

Which factors have an association to the Quality of Life (QoL) of people with acquired Spinal Cord Injury (SCI)? A cross-sectional explorative observational study.

STUDY DESIGN: Cross-sectional explorative observational study. OBJECTIVES: To identify factors which have an association to the self-perceived Quality of Life (QoL) for persons with acquired spinal cord injury (SCI). SETTING: Eight specialized SCI-centers in Germany. The GerSCI survey is the German part of the International Spinal Cord Injury Survey (InSCI). METHODS: Self-disclosure questionnaire, created from the InSCI group, translated and adapted for Germany. The questionnaire collects a very broad range of data and, and due to its design as a self-report, is particularly suitable for the analysis on QoL. Because of the content, which is binding for all participating states, it allows a direct comparability of the results. Included in Germany were 1479 persons with acquired SCI aged 18 years and older. RESULTS: Various factors were identified with high associations to QoL, including changeable and unchangeable ones, such as those of particular importance: pain, sleep problems, sexual dysfunction, age, and time since onset of SCI. Some results confirmed reports of previous studies, others were surprising. CONCLUSION: this study provides an important basis for the planned analysis of the InSCI participating countries in the 6 WHO regions. Germany was able to contribute the largest study population. The concrete study design of InSCI allows us to directly compare data and helps us to improve ourselves within the framework of a "learning health system". Medical measures can be orientated towards the found results, in order to ensure the best possible care and support by the therapeutic team, individually adapted to the person, place of residence and impairment.

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.

Perceived environmental barriers for people with spinal cord injury in Germany and their influence on quality of life.

OBJECTIVE: The German Spinal Cord Injury Survey is part of the International Spinal Cord Injury Survey, which aims to collect data about the life experience of persons with spinal cord injury worldwide. This paper reports on the perceived environmental barriers of the German study population and their associations with quality of life. DESIGN: Cross-sectional explorative observational study using survey data. PARTICIPANTS: A total of 1,479 persons with spinal cord injury aged 18 years and older. METHODS: After descriptive analyses, exploratory factor analysis was used to build groups of environmental barriers. Logistic regressions were performed to assess correlates of perceived environmental barriers. Spearman's correlations were used to analyse the association between perceived barriers and quality of life. RESULTS: Barriers regarding infrastructure had a relatively large impact. Barriers in relation to people's attitudes towards spinal cord injury and the equipment of people with spinal cord injury had a relatively small impact on the lives of people with spinal cord injury. Several subpopulations showed a higher risk in experiencing barriers. Quality of life decreased with increasing experience of barriers. CONCLUSION: The most life-hardening barriers were identified related to infrastructure, a category in which most barriers are modifiable, for example, buildings or transportation.

Utilization of Outpatient Physical and Occupational Therapy in People With Spinal Cord Injury in Germany: Results of the German Spinal Cord Injury Survey.

OBJECTIVE: The aim of the study was to assess factors determining the utilization of physical and occupational therapy in people with spinal cord injury. DESIGN: Data from the German Spinal Cord Injury study conducted in 2017 were analyzed. The 12-mo prevalence of physical therapy and occupational therapy utilization was determined. To identify underlying determinants, multivariable logistic regression was used. RESULTS: Of 1479 participants (response = 26.4%), 72.9% were male, with a mean (SD) age of 55.3 (14.6) yrs and a mean (SD) time since injury of 14.0 (12.0) yrs; 51.2% were people with paraplegia and 66.3% had an incomplete spinal cord injury. In the past 12 mos, 78.1% received physical and 29.3% occupational therapy. Physical therapy and occupational therapy were significantly associated with time since spinal cord injury occurrence, participation in lifelong care programs, and electric wheelchair dependency. Spinal cord injury characteristics, level of impairment, and time since spinal cord injury had a greater impact on occupational therapy than on physical therapy utilization. CONCLUSIONS: The use of physical therapy and occupational therapy is much higher in Germans with spinal cord injury than in the general population and in people with similar neurological conditions. Further research should focus on the frequency of use and the types of interventions. Guidelines for lifelong care should include recommendations on physical therapy and occupational therapy.

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.

[Spinal Cord Injury in Germany - a Survey on the Living and Care Situation of People with Spinal Cord Injury]. / Querschnittlähmung in Deutschland ­ eine Befragung zur Lebens- und Versorgungssituation von Menschen mit Querschnittlähmung.

PURPOSE: Multiple organizations like UN and WHO call for the collection of internationally comparable data on living and supply conditions of people with disabilities. Furthermore, reliable national data are necessary for ensuring appropriate care. Regarding patients with Spinal Cord Injury (SCI) in Germany, only data on diagnostics or therapeutic interventions is currently available. The International Spinal Cord Injury Survey aims at collecting reliable data of people with SCI in 21 countries and developing recommendations for actions to be taken by policy-makers and other decision-makers. METHODS: In 2017, eight specialized SCI-centers across Germany sent a standardized questionnaire to their patients who had diagnosis of SCI, and were older than 18 years (n=5,598). The questionnaire could be completed paper-based or online. RESULTS: 1,479 patients participated in the study and were included in data analysis. On average, participants were 55.3 years (SD=14.6) old, ¾ were male. The mean time of onset of paralysis was 13.9 years. Two thirds of the spinal cord injury causes were traumatic. In 51.2% SCI was classified as paraplegia. The most frequently cited health problem was sexual dysfunction. Medical treatment for this problem was rarely used. Serious environmental barriers were the inadequate accessibility of private households and public places. 42.5% of the respondents in working age were employed, which is 10% less than in Switzerland. DISCUSSION: Serious problems in environmental barriers, medical care and labor market participation were identified for people with SCI. The results will be reported to and discussed with political decision makers and further actors to create solutions. This requires extensive efforts, like modification in building law and home support.

Expression and activity of hyaluronidases HYAL-1, HYAL-2 and HYAL-3 in the human intervertebral disc.

PURPOSE: Hyaluronic acid plays an essential role in water retention of the intervertebral disc (IVD) and thus provides flexibility and shock absorbance in the spine. Hyaluronic acid gets degraded by hyaluronidases (HYALs), and some of the resulting fragments were previously shown to induce an inflammatory and catabolic response in human IVD cells. However, no data currently exist on the expression and activity of HYALs in IVD health and disease. METHODS: Gene expression, protein expression and activity of HYALs were determined in human IVD biopsies with different degrees of degeneration (n = 50 total). Furthermore, freshly isolated human IVD cells (n = 23 total) were stimulated with IL-1ß, TNF-α or H2O2, followed by analysis of HYAL-1, HYAL-2 and HYAL-3 gene expression. RESULTS: Gene expression of HYAL-1 and protein expression of HYAL-2 significantly increased in moderate/severe disc samples when compared to samples with no or low IVD degeneration. HYAL activity was not significantly increased due to high donor-donor variation, but seemed overall higher in the moderate/severe group. An inflammatory environment, as seen during IVD disease, did not affect HYAL-1, HYAL-2 or HYAL-3 expression, whereas exposure to oxidative stress (100 µM H2O2) upregulated HYAL-2 expression relative to untreated controls. CONCLUSION: Although HYAL-1, HYAL-2 and HYAL-3 are all expressed in the IVD, HYAL-2 seems to have the highest pathophysiological relevance. Nonetheless, further studies will be needed to comprehensively elucidate its significance and to determine its potential as a therapeutic target. These slides can be retrieved under Electronic Supplementary Material.

Markedly Deranged Injury Site Metabolism and Impaired Functional Recovery in Acute Spinal Cord Injury Patients With Fever.

OBJECTIVES: To characterize the effect of fever after acute, traumatic spinal cord injury on injury site metabolism and patient outcome. DESIGN: Longitudinal cohort study. In 44 patients (London cohort), we determined the effect of fever on intrathecal injury site metabolism by analyzing 1,767 hours of intraspinal pressure and 759 hours of microdialysis data. We also determined the effect of fever burden, computed for the first 2 weeks in hospital, on neurologic outcome. A distinct cohort of 33 patients (Berlin cohort) was used to independently validate the effect of fever burden on outcome. SETTING: ICUs in London and Berlin. PATIENTS: Seventy-seven patients with acute, traumatic spinal cord injuries. INTERVENTIONS: In the London patients, a pressure probe and a microdialysis catheter were placed intradurally on the surface of the injured cord for up to a week. MEASUREMENTS AND MAIN RESULTS: Fever (> 37.5°C) occurs frequently (37% of the time) after spinal cord injury. High-grade fever (≥ 38°C) was associated with significantly more deranged metabolite levels than normothermia (36.5-37.5°C), that is, lower tissue glucose (median 2.0 vs 3.3 mM), higher lactate (7.8 vs 5.4 mM), higher glutamate (7.8 vs 6.4 µM), and higher lactate-to-pyruvate ratio (38.9 vs 29.3). High-grade fever was particularly detrimental on injury site metabolism when the peripheral leukocyte count was high. In the London and Berlin cohorts, high fever burden correlated with less neurologic improvement. CONCLUSIONS: Early after spinal cord injury, fever is associated with more deranged injury site metabolism than normothermia and worse prognosis.

Outcome analyses of a multimodal treatment approach for deep pressure ulcers in spinal cord injuries: a retrospective cohort study.

STUDY DESIGN: Retrospective observational cohort study. OBJECTIVES: To describe outcomes, risk factors for complications, and relapse rates associated with the multimodal treatment approach for deep pressure ulcers (PUs) grade IV for the ischium, trochanter major, and sacral regions of patients with traumatic and non-traumatic spinal cord injury (SCI). SETTING: The settings comprised two spinal cord units within a maximum care hospital. The treatment of all patients followed the modified interdisciplinary "Basler treatment concept". METHODS: We included all individuals with SCI with a first occurrence of PU grade IV in the buttocks area between August 2008 and December 2012 inclusive, with a maximum follow-up of 3 years. Descriptive, univariate, and bivariate analyses were undertaken, as were group comparisons. RESULTS: In 47 patients aged 18-87 years (mean age: 51 years) a total of 63 fasciocutaneous and myocutaneous flaps were performed. Wound healing was complete after a mean of 34 days (SD = 21). Postoperative mobilisation in a wheelchair was performed after a mean of 46 days (SD = 24). Delayed healing was reported in 18 patients (38%), and revision surgery was necessary in five patients (11%). ASIA impairment scale (AIS) A (p = .001), and male gender (p = .001) were identified as risk factors for delayed wound healing and prolonged inpatient stay. Treatment-associated pneumonia occurred in four cases (11% of all patients, 25% of patients with tetraplegia). Patients were discharged when the time spent sitting in a wheelchair was 2 × 2 h per day; this occurred after a mean of 100 days (SD = 36). PU recurrence was observed in six cases (18%). CONCLUSIONS: Our multimodal treatment concept was found to have complication rates comparable to those in the literature; additionally, this approach might be associated with lower recurrence rates with respect to the literature. To reduce high rates of pneumonia occurrence among patients with tetraplegia, preventive measures need to be established. Further evidence of the efficiency of this complex treatment approach for PU in individuals with SCI is needed.

Acute transient spinal paralysis and cardiac symptoms following an accidental epidural potassium infusion - a case report.

BACKGROUND: To describe a case of an accidental epidural potassium infusion leading to an acute transient spinal paralysis and cardiac symptoms and review the literature on that topic. CASE PRESENTATION: We report the case of an accidental infusion of 900 mg potassium chloride 7.45% (KCl) into the epidural space, which occurred during epidural analgesia in a 74-year-old patient suffering from immobilization due to lumbar back pain as well as from a paralytic Ileus. The event was resulting in vegetative symptoms, such as tachycardia and hypertension accompanied by a motor complete tetraplegia (AIS B) sub C2 with respiratory depression. The endotracheal intubation was necessary. The patient was treated with 40 mg dexamethasone intravenously, as well an epidural lavage with sodium chloride solution 0.9% (NaCl) through the epidural catheter. The neurologic symptoms completely resolved within five days. An elevation of troponin-T values and a reduced left ventricular ejection fraction (LVEF) of 40% accompanied by transient pectanginous pain were documented. An exertional dyspnea remained. CONCLUSIONS: A symptom complex with elevated sympathetic nervous system activity up to a stress cardiomyopathy is possible following epidural potassium infusion. Additionally, generalized pain and muscle spasticity evolve and a progressive acute spinal cord injury syndrome can occur within minutes, accompanied by respiratory depression. Treatment consists of early intensive care and the symptomatic therapy of the associated symptoms, leading in most of the reported cases to a good clinical outcome.

Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex.

Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI. Prophylactic adrenalectomy completely prevented SCI-induced glucocorticoid excess and lymphocyte depletion but did not prevent pneumonia. When adrenalectomized mice were transplanted with denervated adrenal glands to restore physiologic glucocorticoid levels, the animals were completely protected from pneumonia. These findings identify a maladaptive sympathetic-neuroendocrine adrenal reflex mediating immunosuppression after SCI, implying that therapeutic normalization of the glucocorticoid and catecholamine imbalance in SCI patients could be a strategy to prevent detrimental infections.

Natural Killer (NK) Cell Functionality after human Spinal Cord Injury (SCI): protocol of a prospective, longitudinal study.

BACKGROUND: Natural killer (NK) cells comprise the main components of lymphocyte-mediated nonspecific immunity. Through their effector function they play a crucial role combating bacterial and viral challenges. They are also thought to be key contributors to the systemic spinal cord injury-induced immune-deficiency syndrome (SCI-IDS). SCI-IDS increases susceptibility to infection and extends to the post-acute and chronic phases after SCI. METHODS AND DESIGN: The prospective study of NK cell function after traumatic SCI was carried out in two centers in Berlin, Germany. SCI patients and control patients with neurologically silent vertebral fracture also undergoing surgical stabilization were enrolled. Furthermore healthy controls were included to provide reference data. The NK cell function was assessed at 7 (5-9) days, 14 days (11-28) days, and 10 (8-12) weeks post-trauma. Clinical documentation included the American Spinal Injury Association (ASIA) impairment scale (AIS), neurological level of injury, infection status, concomitant injury, and medications. The primary endpoint of the study is CD107a expression by NK cells (cytotoxicity marker) 8-12 weeks following SCI. Secondary endpoints are the NK cell's TNF-α and IFN-γ production by the NK cells 8-12 weeks following SCI. DISCUSSION: The protocol of this study was developed to investigate the hypotheses whether i) SCI impairs NK cell function throughout the post-acute and sub-acute phases after SCI and ii) the degree of impairment relates to lesion height and severity. A deeper understanding of the SCI-IDS is crucial to enable strategies for prevention of infections, which are associated with poor neurological outcome and elevated mortality. TRIAL REGISTRATION: DRKS00009855 .

SCISSOR-Spinal Cord Injury Study on Small molecule-derived Rho inhibition: a clinical study protocol.

INTRODUCTION: The approved analgesic and anti-inflammatory drugs ibuprofen and indometacin block the small GTPase RhoA, a key enzyme that impedes axonal sprouting after axonal damage. Inhibition of the Rho pathway in a central nervous system-effective manner requires higher dosages compared with orthodox cyclooxygenase-blocking effects. Preclinical studies on spinal cord injury (SCI) imply improved motor recovery after ibuprofen/indometacin-mediated Rho inhibition. This has been reassessed by a meta-analysis of the underlying experimental evidence, which indicates an overall effect size of 20.2% regarding motor outcome achieved after ibuprofen/indometacin treatment compared with vehicle controls. In addition, ibuprofen/indometacin may also limit sickness behaviour, non-neurogenic systemic inflammatory response syndrome (SIRS), neuropathic pain and heterotopic ossifications after SCI. Consequently, 'small molecule'-mediated Rho inhibition after acute SCI warrants clinical investigation. METHODS AND ANALYSIS: Protocol of an investigator-initiated clinical open-label pilot trial on high-dose ibuprofen treatment after acute traumatic, motor-complete SCI. A sample of n=12 patients will be enrolled in two cohorts treated with 2400 mg/day ibuprofen for 4 or 12 weeks, respectively. The primary safety end point is an occurrence of serious adverse events, primarily gastroduodenal bleedings. Secondary end points are pharmacokinetics, feasibility and preliminary effects on neurological recovery, neuropathic pain and heterotopic ossifications. The primary safety analysis is based on the incidence of severe gastrointestinal bleedings. Additional analyses will be mainly descriptive and casuistic. ETHICS AND DISSEMINATION: The clinical trial protocol was approved by the responsible German state Ethics Board, and the Federal Institute for Drugs and Medical Devices. The study complies with the Declaration of Helsinki, the principles of Good Clinical Practice and all further applicable regulations. This safety and pharmacokinetics trial informs the planning of a subsequent randomised controlled trial. Regardless of the result of the primary and secondary outcome assessments, the clinical trial will be reported as a publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT02096913; Pre-results.