Minimally invasive tubular removal of spinal schwannoma and neurofibroma - a case series of 49 patients and review of the literature.

To evaluate the efficacy and safety of minimally invasive tubular removal of spinal schwannoma and neurofibroma. In this single-centre study, we retrospectively analysed 49 consecutive patients who underwent minimally invasive removal of a total of 51 benign spinal nerve sheath tumors using a non-expandable (n = 18) or expandable tubular retractor (n = 33) retractor system between June 2007 and December 2019. The extent of resection, surgical complications, neurological outcome, operative time, and estimated blood loss were recorded. Histopathology revealed 41 schwannomas and 10 neurofibromas. After a mean follow-up of 30.8 months, postoperative MRI showed gross total resection in 93.7%, and subtotal resection in 6.3% of the tumors. Three patients were lost to follow up. Of the subtotal resections, one was a schwannoma (2.4% subtotal resections in schwannomas) and two were neurofibromas (20.0% subtotal resections in neurofibromas). Intraspinal and paraspinal tumor localizations were equally accessible by minimally invasive tubular surgery. Conversion to open surgery was not required in any case. The mean operative time was 167 ± 68 min, and estimated blood loss was 138 ± 145 ml. We observed no major surgical complications. Spinal schwannoma and neurofibroma can be removed effectively and safely using a minimally invasive tubular approach, with satisfying extent of tumor resection comparable to the conventional open surgical technique and no increased risk for neurological deterioration.

Effect-Size Discrepancies in Literature Versus Raw Datasets from Experimental Spinal Cord Injury Studies: A CLIMBER Meta-Analysis.

Translation of spinal cord injury (SCI) therapeutics from pre-clinical animal studies into human studies is challenged by effect size variability, irreproducibility, and misalignment of evidence used by pre-clinical versus clinical literature. Clinical literature values reproducibility, with the highest grade evidence (class 1) consisting of meta-analysis demonstrating large therapeutic efficacy replicating across multiple studies. Conversely, pre-clinical literature values novelty over replication and lacks rigorous meta-analyses to assess reproducibility of effect sizes across multiple articles. Here, we applied modified clinical meta-analysis methods to pre-clinical studies, comparing effect sizes extracted from published literature to raw data on individual animals from these same studies. Literature-extracted data (LED) from numerical and graphical outcomes reported in publications were compared with individual animal data (IAD) deposited in a federally supported repository of SCI data. The animal groups from the IAD were matched with the same cohorts in the LED for a direct comparison. We applied random-effects meta-analysis to evaluate predictors of neuroconversion in LED versus IAD. We included publications with common injury models (contusive injuries) and standardized end-points (open field assessments). The extraction of data from 25 published articles yielded n = 1841 subjects, whereas IAD from these same articles included n = 2441 subjects. We observed differences in the number of experimental groups and animals per group, insufficient reporting of dropout animals, and missing information on experimental details. Meta-analysis revealed differences in effect sizes across LED versus IAD stratifications, for instance, severe injuries had the largest effect size in LED (standardized mean difference [SMD = 4.92]), but mild injuries had the largest effect size in IAD (SMD = 6.06). Publications with smaller sample sizes yielded larger effect sizes, while studies with larger sample sizes had smaller effects. The results demonstrate the feasibility of combining IAD analysis with traditional LED meta-analysis to assess effect size reproducibility in SCI.

Quantification of cervical spinal stenosis by automated 3D MRI segmentation of spinal cord and cerebrospinal fluid space.

DESIGN: Prospective diagnostic study. OBJECTIVES: Anatomical evaluation and graduation of the severity of spinal stenosis is essential in degenerative cervical spine disease. In clinical practice, this is subjectively categorized on cervical MRI lacking an objective and reliable classification. We implemented a fully-automated quantification of spinal canal compromise through 3D T2-weighted MRI segmentation. SETTING: Medical Center - University of Freiburg, Germany. METHODS: Evaluation of 202 participants receiving 3D T2-weighted MRI of the cervical spine. Segments C2/3 to C6/7 were analyzed for spinal cord and cerebrospinal fluid space volume through a fully-automated segmentation based on a trained deep convolutional neural network. Spinal canal narrowing was characterized by relative values, across sever segments as adapted Maximal Canal Compromise (aMCC), and within the index segment as adapted Spinal Cord Occupation Ratio (aSCOR). Additionally, all segments were subjectively categorized by three observers as "no", "relative" or "absolute" stenosis. Computed scores were applied on the subjective categorization. RESULTS: 798 (79.0%) segments were subjectively categorized as "no" stenosis, 85 (8.4%) as "relative" stenosis, and 127 (12.6%) as "absolute" stenosis. The calculated scores revealed significant differences between each category (p ≤ 0.001). Youden's Index analysis of ROC curves revealed optimal cut-offs to distinguish between "no" and "relative" stenosis for aMCC = 1.18 and aSCOR = 36.9%, and between "relative" and "absolute" stenosis for aMCC = 1.54 and aSCOR = 49.3%. CONCLUSION: The presented fully-automated segmentation algorithm provides high diagnostic accuracy and objective classification of cervical spinal stenosis. The calculated cut-offs can be used for convenient radiological quantification of the severity of spinal canal compromise in clinical routine.

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.

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.

The Impact of Implementing a Radiation-Sparing Protocol for Percutaneous Kyphoplasty-A Prospective Dosemetric Study.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: The purpose of this prospective study was to evaluate a protocol for radiation-sparing kyphoplasty by assessing dosemetrically recorded radiation exposures to both patient and surgeon. METHODS: This prospective clinical study examines the radiation exposure to patient and surgeon during single-level kyphoplasty in 32 thoracolumbar osteoporotic vertebral body fractures (12 OF 2, 9 OF 3, 11 OF 4 types) using a radiation aware surgical protocol between May 2017 and November 2019. The radiation exposure was measured at different locations using film, eye lens and ring dosemeters. Dose values are reported under consideration of lower detection limits of each dosemeter type. RESULTS: A high proportion of dosemeter readings was below the lower detection limits, especially for the surgeon (>90%). Radiation exposure to the surgeon was highest at the unprotected thyroid gland (0.053 ± 0.047 mSv), however only slightly above the lower detection limit of dosemeters (0.044 mSv). Radiation exposure to the patient was highest at the chest (0.349 ± 0.414 mSv) and the gonad (0.186 ± 0.262 mSv). Fluoroscopy time, dose area product and number of fluoroscopic images were 46.0 ± 17.9 sec, 124 ± 109 cGy×cm2, and 35 ± 13 per kyphoplasty, respectively. Back pain significantly improved from 6.8 ± 1.6 to 2.5 ± 1.7 on the numeric rating scale on the first postoperative day (P < 0.0001). CONCLUSIONS: The implementation of a strict intraoperative radiation protection protocol allows for safely performed kyphoplasty with ultra-low radiation exposure for the patient and surgeon without exceeding the annual occupational dose limits. TRIAL REGISTRATION: The study was registered in the German Clinical Trials Register (DRKS00011908, registration date 16/05/2017).

Effectiveness of biomaterial-based combination strategies for spinal cord repair - a systematic review and meta-analysis of preclinical literature.

STUDY DESIGN: Systematic review and meta-analysis of preclinical literature. OBJECTIVES: To assess the effects of biomaterial-based combination (BMC) strategies for the treatment of Spinal Cord Injury (SCI), the effects of individual biomaterials in the context of BMC strategies, and the factors influencing their efficacy. To assess the effects of different preclinical testing paradigms in BMC strategies. METHODS: We performed a systematic literature search of Embase, Web of Science and PubMed. All controlled preclinical studies describing an in vivo or in vitro model of SCI that tested a biomaterial in combination with at least one other regenerative strategy (cells, drugs, or both) were included. Two review authors conducted the study selection independently, extracted study characteristics independently and assessed study quality using a modified CAMARADES checklist. Effect size measures were combined using random-effects models and heterogeneity was explored using meta-regression with tau2, I2 and R2 statistics. We tested for small-study effects using funnel plot-based methods. RESULTS: 134 publications were included, testing over 100 different BMC strategies. Overall, treatment with BMC therapies improved locomotor recovery by 25.3% (95% CI, 20.3-30.3; n = 102) and in vivo axonal regeneration by 1.6 SD (95% CI 1.2-2 SD; n = 117) in comparison with injury only controls. CONCLUSION: BMC strategies improve locomotor outcomes after experimental SCI. Our comprehensive study highlights gaps in current knowledge and provides a foundation for the design of future experiments.

The challenge of measuring spinopelvic parameters: inter-rater reliability before and after minimally invasive lumbar spondylodesis.

BACKGROUND: The common manual measurement technique of spinal sagittal alignment on X-rays is susceptible to rater-dependent variability, which has not been adequately considered in previous publications. This study investigates the effect of those variations in the characterization of patients receiving lumbar spondylodesis. METHODS: General alignment parameters on pre- and postoperative X-rays were evaluated by four raters in 43 prospectively sampled patients undergoing monolevel spondylodesis. The Intra-class Correlation Coefficient (ICC) for each rater pair and all raters together was calculated for inter-rater reliability. For the operation-induced change of the sagittal alignment in every patient the Wilcoxon test was applied to compare for each rater separately. RESULTS: The ICCs were "good" (>0.75) to "excellent" (>0.9) for all raters together and for 45 of the 48 single rater pairs (93.75%). All revealed a significant increase of the addressed segmental lordosis and disc height and no significant change for spinopelvic parameters and sagittal vertical axis from pre- to postoperative. The lumbar lordosis showed a significant increase through the operation of +2.5° (p = 0.014) and +3.7° (p = 0.015) in two raters and no difference for the other ones (+2.1°, p = 0.171; -2.2°, p = 0.522). CONCLUSIONS: The pre- to postoperative change of lumbar lordosis revealed different significance levels for different raters, although the ICCs were formally good. Accordingly, the evaluation by only one rater would lead to different conclusions. Due to this susceptibility of alignment measurements to rater-dependent variability, the exact evaluation process should be described in every publication and the consistency of significant results be validated through multiple raters. TRIALS REGISTRATION: The trial was approved by the local ethics committee and listed at the national clinical trials register ( DRKS00004514 , date of registration: 08/11/2012).

Cranial facet joint injuries in percutaneous lumbar pedicle screw placement: a matched-pair analysis comparing intraoperative 3D navigation and conventional fluoroscopy.

PURPOSE: The violation of the cranial adjacent facet is a frequent complication in lumbar instrumentations and can induce local pain and adjacent segment disease. Minimally invasive screw implantation is often stated as risk factor in comparison with open approaches. Percutaneous pedicle screw placement (PPSP) can be performed using single X-ray images (fluoroscopy) or intraoperative 3D navigation. The study compares top-level screws in percutaneous lumbar instrumentations regarding facet violations and screw pedicle position using navigation or fluoroscopy. METHODS: Patients after lumbar PPSP were retrospectively separated according to the intraoperative technique: navigation (NAV) or fluoroscopy (FLUORO). Two blinded investigators graded the top-level screws regarding facet violations and pedicle breach in postoperative CT scans. Subsequent matched cohort analysis was performed for comparable groups. RESULTS: Evaluating 768 screws, we assessed 70 (9.1%) facet violations. Overall, 186 (24.2%) screws were implanted using navigation. There was no significant difference in the rate of facet violations between both imaging groups (NAV 19/186, 10.2%, FLUORO 51/582, 8.8%, p = 0.55). Totally, 728 (94.8%) of all screws showed a correct pedicle position. Most of the 40 unfavorable pedicle positions were placed by fluoroscopy (NAV 4/186, 2.2%, FLUORO 36/582, 6.6%, p = 0.03). The matched cohorts verified these results (facet violations: NAV 19/186, 10.2%, FLUORO 18/186, 9.7%, p = 0.55; pedicle penetrations: NAV 4/186, 2.2%, FLUORO 12/186, 6.9%, p = 0.04). CONCLUSIONS: Both intraoperative imaging techniques allow lumbar PPSP with low rates of cranial facet violations if the surgeon intends to preserve facet integrity. Navigation was superior concerning accurate pedicle screw position, but could not significantly prevent facet violations.

Noninvasive patient tracker mask for spinal 3D navigation: does the required large-volume 3D scan involve a considerably increased radiation exposure?

OBJECTIVE: Intraoperative 3D imaging and navigation is increasingly used for minimally invasive spine surgery. A novel, noninvasive patient tracker that is adhered as a mask on the skin for 3D navigation necessitates a larger intraoperative 3D image set for appropriate referencing. This enlarged 3D image data set can be acquired by a state-of-the-art 3D C-arm device that is equipped with a large flat-panel detector. However, the presumably associated higher radiation exposure to the patient has essentially not yet been investigated and is therefore the objective of this study. METHODS: Patients were retrospectively included if a thoracolumbar 3D scan was performed intraoperatively between 2016 and 2019 using a 3D C-arm with a large 30 × 30-cm flat-panel detector (3D scan volume 4096 cm3) or a 3D C-arm with a smaller 20 × 20-cm flat-panel detector (3D scan volume 2097 cm3), and the dose area product was available for the 3D scan. Additionally, the fluoroscopy time and the number of fluoroscopic images per 3D scan, as well as the BMI of the patients, were recorded. RESULTS: The authors compared 62 intraoperative thoracolumbar 3D scans using the 3D C-arm with a large flat-panel detector and 12 3D scans using the 3D C-arm with a small flat-panel detector. Overall, the 3D C-arm with a large flat-panel detector required more fluoroscopic images per scan (mean 389.0 ± 8.4 vs 117.0 ± 4.6, p < 0.0001), leading to a significantly higher dose area product (mean 1028.6 ± 767.9 vs 457.1 ± 118.9 cGy × cm2, p = 0.0044). CONCLUSIONS: The novel, noninvasive patient tracker mask facilitates intraoperative 3D navigation while eliminating the need for an additional skin incision with detachment of the autochthonous muscles. However, the use of this patient tracker mask requires a larger intraoperative 3D image data set for accurate registration, resulting in a 2.25 times higher radiation exposure to the patient. The use of the patient tracker mask should thus be based on an individual decision, especially taking into considering the radiation exposure and extent of instrumentation.

Enhanced axonal response of mitochondria to demyelination offers neuroprotection: implications for multiple sclerosis.

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.

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.

Correction to: One decade of glioblastoma multiforme surgery in 342 elderly patients: what have we learned?

There was a typo in the third author's name in the initial online publication.

One decade of glioblastoma multiforme surgery in 342 elderly patients: what have we learned?

INTRODUCTION: Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults with peak incidence in patients older than 65 years. These patients are mostly underrepresented in clinical trials and often undertreated due to concomitant diseases. Recently, different therapeutic approaches for elderly patients with GBM were discussed. To date, there is no defined standard treatment. The aim of the present study is to evaluate the functional and oncological outcome in surgical treatment of elderly patients. MATERIALS AND METHODS: A total of 342 elderly patients aged ≥ 65 years were retrospectively analyzed in our neurosurgical center. Surgical therapy, adjuvant treatment, overall survival (OS) and functional outcome using Karnofsky performance scale (KPS) and Neurological assessment of neuro-oncology-score were analyzed. RESULTS: The median age at GBM diagnosis was 73.4 (IQR 9.28) years. Median overall survival was 7.5 (CI 95% 6.0-9.1) months and median preoperative or postoperative KPS was 80 (IQR 20). Surgical resection was performed in 216 (63.2%) patients, in 125 patients (36.5%) patients a stereotactic biopsy was performed. The median OS was significantly higher in patients with gross total resection (GTR) compared to partial resection and biopsy (10.8 months; CI 95% 9.5-12.3). Patients with combined radio- and chemo-therapy (RCT) showed significant longer OS, particularly MGMT-negative GBM. Higher preoperative KPS was found to be associated with improved overall survival. CONCLUSION: GTR and adjuvant combined RCT provides benefits for overall survival in elderly patients. Therapy decision should be made in regard to preoperative functional status instead of biological age.

Long-term functional outcome in patients with acquired infections after acute spinal cord injury.

OBJECTIVE: To investigate whether prevalent hospital-acquired pneumonia and wound infection affect the clinical long-term outcome after acute traumatic spinal cord injury (SCI). METHODS: This was a longitudinal cohort study within the prospective multicenter National Spinal Cord Injury Database (Birmingham, Alabama). We screened datasets of 3,834 patients enrolled in 20 trial centers from 1995 to 2005 followed up until 2016. Eligibility criteria were cervical SCI and American Spinal Cord Injury Association impairment scale A, B, and C. Pneumonia or postoperative wound infections (Pn/Wi) acquired during acute medical care/inpatient rehabilitation were analyzed for their association with changes in the motor items of the Functional Independence Measure (FIMmotor) using regression models (primary endpoint 5-year follow-up). Pn/Wi-related mortality was assessed as a secondary endpoint (10-year follow-up). RESULTS: A total of 1,203 patients met the eligibility criteria. During hospitalization, 564 patients (47%) developed Pn/Wi (pneumonia n = 540; postoperative wound infection n = 11; pneumonia and postoperative wound infection n = 13). Adjusted linear mixed models after multiple imputation revealed that Pn/Wi are significantly associated with lower gain in FIMmotor up to 5 years after SCI (-7.4 points, 95% confidence interval [CI] -11.5 to -3.3). Adjusted Cox regression identified Pn/Wi as a highly significant risk factor for death up to 10 years after SCI (hazard ratio 1.65, 95% CI 1.26 to 2.16). CONCLUSION: Hospital-acquired Pn/Wi are predictive of propagated disability and mortality after SCI. Pn/Wi qualify as a potent and targetable outcome-modifying factor. Pn/Wi prevention constitutes a viable strategy to protect functional recovery and reduce mortality. Pn/Wi can be considered as rehabilitation confounders in clinical trials.

Study protocol - A systematic review and meta-analysis of hypothermia in experimental traumatic brain injury: Why have promising animal studies not been replicated in pragmatic clinical trials?

Traumatic brain injury (TBI) is a major cause of death and permanent disability. Systemic hypothermia, a treatment used in TBI for many decades, has recently been found to be associated with neutral or unfavourable clinical outcomes despite apparently promising preclinical research. Systematic review and meta-analysis is a tool to summarize literature and observe trends in experimental design and quality that underpin its general conclusions. Here we aim to use these techniques to describe the use of hypothermia in animal TBI models, collating data relating to outcome and both study design and quality. From here we intend to observe correlations between features and attempt to explain any discrepancies found between animal and clinical data. This protocol describes the relevant methodology in detail.

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.

Olfactory Ensheathing Cell Transplantation in Experimental Spinal Cord Injury: Effect size and Reporting Bias of 62 Experimental Treatments: A Systematic Review and Meta-Analysis.

Olfactory ensheathing cell (OEC) transplantation is a candidate cellular treatment approach for human spinal cord injury (SCI) due to their unique regenerative potential and autologous origin. The objective of this study was, through a meta-epidemiologic approach, (i) to assess the efficacy of OEC transplantation on locomotor recovery after traumatic experimental SCI and (ii) to estimate the likelihood of reporting bias and/or missing data. A study protocol was finalized before data collection. Embedded into a systematic review and meta-analysis, we conducted a literature research of databases including PubMed, EMBASE, and ISI Web of Science from 1949/01 to 2014/10 with no language restrictions, screened by two independent investigators. Studies were included if they assessed neurobehavioral improvement after traumatic experimental SCI, administrated no combined interventions, and reported the number of animals in the treatment and control group. Individual effect sizes were pooled using a random effects model. Details regarding the study design were extracted and impact of these on locomotor outcome was assessed by meta-regression. Missing data (reporting bias) was determined by Egger regression and Funnel-plotting. The primary study outcome assessed was improvement in locomotor function at the final time point of measurement. We included 49 studies (62 experiments, 1,164 animals) in the final analysis. The overall improvement in locomotor function after OEC transplantation, measured using the Basso, Beattie, and Bresnahan (BBB) score, was 20.3% (95% CI 17.8-29.5). One missing study was imputed by trim and fill analysis, suggesting only slight publication bias and reducing the overall effect to a 19.2% improvement of locomotor activity. Dose-response ratio supports neurobiological plausibility. Studies were assessed using a 9-point item quality score, resulting in a median score of 5 (interquartile range [IQR] 3-5). In conclusion, OEC transplantation exerts considerable beneficial effects on neurobehavioral recovery after traumatic experimental SCI. Publication bias was minimal and affirms the translational potential of efficacy, but safety cannot be adequately assessed. The data justify OECs as a cellular substrate to develop and optimize minimally invasive and safe cellular transplantation paradigms for the lesioned spinal cord embedded into state-of-the-art Phase I/II clinical trial design studies for human SCI.