Antibody-mediated autoimmunity in symptom-based disorders: position statement and proceedings from an international workshop.

A 2-day closed workshop was held in Liverpool, United Kingdom, to discuss the results of research concerning symptom-based disorders (SBDs) caused by autoantibodies, share technical knowledge, and consider future plans. Twenty-two speakers and 14 additional participants attended. This workshop set out to consolidate knowledge about the contribution of autoantibodies to SBDs. Persuasive evidence for a causative role of autoantibodies in disease often derives from experimental "passive transfer" approaches, as first established in neurological research. Here, serum immunoglobulin (IgM or IgG) is purified from donated blood and transferred to rodents, either systemically or intrathecally. Rodents are then assessed for the expression of phenotypes resembling the human condition; successful phenotype transfer is considered supportive of or proof for autoimmune pathology. Workshop participants discussed passive transfer models and wider evidence for autoantibody contribution to a range of SBDs. Clinical trials testing autoantibody reduction were presented. Cornerstones of both experimental approaches and clinical trial parameters in this field were distilled and presented in this article. Mounting evidence suggests that immunoglobulin transfer from patient donors often induces the respective SBD phenotype in rodents. Understanding antibody binding epitopes and downstream mechanisms will require substantial research efforts, but treatments to reduce antibody titres can already now be evaluated.

Neurological recovery after early versus delayed surgical decompression for acute traumatic spinal cord injury.

The aim of this study was to determine whether early surgical treatment results in better neurological recovery 12 months after injury than late surgical treatment in patients with acute traumatic spinal cord injury (tSCI). Patients with tSCI requiring surgical spinal decompression presenting to 17 centres in Europe were recruited. Depending on the timing of decompression, patients were divided into early (≤ 12 hours after injury) and late (> 12 hours and < 14 days after injury) groups. The American Spinal Injury Association neurological (ASIA) examination was performed at baseline (after injury but before decompression) and at 12 months. The primary endpoint was the change in Lower Extremity Motor Score (LEMS) from baseline to 12 months. The final analyses comprised 159 patients in the early and 135 in the late group. Patients in the early group had significantly more severe neurological impairment before surgical treatment. For unadjusted complete-case analysis, mean change in LEMS was 15.6 (95% confidence interval (CI) 12.1 to 19.0) in the early and 11.3 (95% CI 8.3 to 14.3) in the late group, with a mean between-group difference of 4.3 (95% CI -0.3 to 8.8). Using multiply imputed data adjusting for baseline LEMS, baseline ASIA Impairment Scale (AIS), and propensity score, the mean between-group difference in the change in LEMS decreased to 2.2 (95% CI -1.5 to 5.9). Compared to late surgical decompression, early surgical decompression following acute tSCI did not result in statistically significant or clinically meaningful neurological improvements 12 months after injury. These results, however, do not impact the well-established need for acute, non-surgical tSCI management. This is the first study to highlight that a combination of baseline imbalances, ceiling effects, and loss to follow-up rates may yield an overestimate of the effect of early surgical decompression in unadjusted analyses, which underpins the importance of adjusted statistical analyses in acute tSCI research.

Thromboembolism in the Sub-Acute Phase of Spinal Cord Injury: A Systematic Review of the Literature.

To review the evidence of thromboembolism incidence and prophylaxis in the sub-acute phase of spinal cord injury (SCI) 3-6 months post injury. All observational and experimental studies with any length of follow-up and no limitations on language or publication status published up to March 2015 were included. Two review authors independently selected trials for inclusion and extracted data. Outcomes studied were incidence of pulmonary embolism (PE) and deep vein thrombosis (DVT) in the sub-acute phase of SCI. The secondary outcome was type of thromboprophylaxis. Our search identified 4305 references and seven articles that met the inclusion criteria. Five papers reported PE events and three papers reported DVT events in the sub-acute phase of SCI. Studies were heterogeneous in populations, design and outcome reporting, therefore a meta-analysis was not performed. The included studies report a PE incidence of 0.5%-6.0% and DVT incidence of 2.0%-8.0% in the sub-acute phase of SCI. Thromboprophylaxis was poorly reported. Spinal patients continue to have a significant risk of PE and DVT after the acute period of their injury. Clinicians are advised to have a low threshold for suspecting venous thromboembolism in the sub-acute phase of SCI and to continue prophylactic anticoagulation therapy for a longer period of time.

Lower-limb exoskeletons for individuals with chronic spinal cord injury: findings from a feasibility study.

OBJECTIVE: To assess the feasibility of conducting a well-powered trial evaluating the neurological and functional effects of using an exoskeleton in individuals with chronic spinal cord injury. DESIGN: A longitudinal, prospective, self-controlled feasibility study. SETTING: Specialist Spinal Cord Injuries Centre, UK; 8 months during 2013-2014. SUBJECTS: Individuals with chronic motor complete or incomplete spinal cord injury. INTERVENTIONS: Enrolled subjects were assigned to 20 exoskeleton (ReWalk™, Argo Medical Technologies Ltd, Yokneam Ilit, Israel) training sessions over a 10-week training period. MAIN MEASURES: Feasibility measures, clinical and mobility outcome measures and measures appraising subjects' disability and attitude towards assistive technology were assessed before, during and after the study. Descriptive statistics were applied. RESULTS: Out of 60 candidates, ten (17%) were enrolled and five (8%) completed the training programme. Primary reasons for not enrolling were ineligibility (n = 24, 40%) and limited interest to engage in a 10-week training programme (n = 16, 27%). Five out of ten enrolled subjects experienced grade I/II skin aberrations. While walking speeds were higher and walking distances were longer in all exoskeleton users when compared with non-use, the exoskeleton did generally not meet subjects' high expectations in terms of perceived benefits. CONCLUSIONS: The conduct of a controlled trial evaluating the benefits of using exoskeletons that require a lengthy user-commitment to training of individuals with chronic motor complete or incomplete spinal cord injury comes with considerable feasibility challenges. Vigilance is required for preventing and detecting medical complications in spinal cord injury exoskeleton users.

The effects of the timing of spinal surgery after traumatic spinal cord injury: a systematic review and meta-analysis.

Abstract The debate over the effects of the timing of surgical spinal decompression after traumatic spinal cord injury (tSCI) has remained unresolved for over a century. The aim of the current study was to perform a systematic review and quality-adjusted meta-analysis of studies evaluating the effects of the timing of spinal surgery after tSCI. Studies were searched for through the MEDLINE(®) database (1966 to August 2012) and a 15-item, tailored scoring system was used for assessing the included studies' susceptibility to bias. Random effects and quality effects meta-analyses were performed. Models were tested for robustness using one way and criterion-based sensitivity analysis and funnel plots. Results are presented as weighted mean differences (WMDs) and odds ratios (ORs) with 95% confidence intervals (CIs). A total of 18 studies were analyzed. Heterogeneity was evident among the studies included. Quality effects models showed that - when compared with "late" surgery - "early" spinal surgery was significantly associated with a higher total motor score improvement (WMD: 5.94 points, 95% CI:0.74,11.15) in seven studies, neurological improvement rate (OR: 2.23, 95% CI:1.35,3.67) in six studies, and shorter length of hospital stay (WMD: -9.98 days, 95% CI:-13.10,-6.85) in six studies. However, one way and criterion-based sensitivity analyses demonstrated a profound lack of robustness among pooled estimates. Funnel plots showed significant proof of publication bias. In conclusion, despite the fact that "early" spinal surgery was significantly associated with improved neurological and length of stay outcomes, the evidence supporting "early" spinal surgery after tSCI lacks robustness as a result of different sources of heterogeneity within and between original studies. Where the conduct of a surgical, randomized controlled trial seems to be an unfeasible undertaking in acute tSCI, methodological safeguards require the utmost attention in future cohort studies. (Prospero registration number: PROSPERO CRD42012003182. See also http://www.crd.york.ac.uk/NIHR_PROSPERO/ ).

The Subaxial Cervical Spine Injury Classification System: an external agreement validation study.

BACKGROUND CONTEXT: In 2007, the Subaxial Cervical Spine Injury Classification (SLIC) system was introduced demonstrating moderate reliability in an internal validation study. PURPOSE: To assess the agreement on the SLIC system using clinical data from a spinal trauma population and whether the SLIC treatment algorithm outcome improved agreement on treatment decisions among surgeons. STUDY DESIGN: An external classification validation study. PATIENT SAMPLE: Twelve spinal surgeons (five consultants and seven fellows) assessed 51 randomly selected cases. OUTCOME MEASURES: Raw agreement, Fleiss kappa, and intraclass correlation coefficient statistics were used for reliability analysis. Majority rules and latent class modeling were used for accuracy analysis. METHODS: Fifty-one randomly selected cases with significant injuries of the cervical spine from a prospective consecutive series of trauma patients were assessed using the SLIC system. Neurologic details, plain radiographs, and computed tomography scans were available for all cases as well as magnetic resonance imaging in 21 cases (41%). No funds were received in support of this study. The authors have no conflict of interest in the subject of this article. RESULTS: The inter-rater agreement on the most severely affected level of injury was strong (κ=0.76). The agreement on the morphologic injury characteristics was poor (κ=0.29) and agreement on the integrity of the discoligamentous complex was average (κ=0.46). The inter-rater agreement on the treatment verdict after the total SLIC injury severity score was slightly lower than the surgeons' agreement on personal treatment preference (κ=0.55 vs. κ=0.63). Latent class analysis was not converging and did not present accurate estimations of the true classification categories. Based on these findings, no second survey for testing intrarater agreement was performed. CONCLUSIONS: We found poor agreement on the morphologic injury characteristics of the SLIC system, and its treatment algorithm showed no improved agreement on treatment decisions among surgeons. The authors discuss that the reproducibility of the SLIC system is likely to improve when unambiguous true morphologic injury characteristics are being implemented.

The precision, accuracy and validity of detecting posterior ligamentous complex injuries of the thoracic and lumbar spine: a critical appraisal of the literature.

PURPOSE: The diagnostic assessment and prognostic value of the posterior ligamentous complex (PLC) remains a controversial topic in the management of patients with thoracolumbar spinal injury. The purpose of this review was to critically appraise the literature and present an overview of the: (1) precision, (2) accuracy, and (3) validity of detecting PLC injuries in patients with thoracic and lumbar spine trauma. METHODS: Studies evaluating the precision, accuracy and/or validity of detecting and managing PLC injuries in patients with thoracic and/or lumbar spine injuries were searched through the Medline database (1966 to September 2011). References were retrieved and evaluated individually and independently by two authors. RESULTS: Twenty-one eligible studies were identified. Few studies reported the use of countermeasures for sampling and measurement bias. In nine agreement studies, the PLC was assessed in various ways, ranging from use of booklets to a complete set of diagnostic imaging. Inter-rater and intra-rater kappa values ranged from 0.188 to 0.915 and 0.455 to 0.840, respectively. In nine accuracy studies, magnetic resonance (MR) imaging was most often (n = 6) compared with intra-operative findings. In general, MR imaging tended to demonstrate relatively high negative predictive values and relatively low positive predictive values for PLC injuries. CONCLUSIONS: A wide variety of methods have been applied in the evaluation of precision and accuracy of PLC injury detection, leaving spinal surgeons with a multitude of variable results. There is scant clinical evidence demonstrating the true prognostic value of detected PLC injuries in patients with thoracic and lumbar spine injuries. We recommend the conduct of longitudinal clinical follow-up studies on those cases assessed for precision and/or accuracy of PLC injuries.

A methodological systematic review on surgical site infections following spinal surgery: part 2: prophylactic treatments.

STUDY DESIGN: A methodological systematic review. OBJECTIVE: To critically appraise the validity of preventive effects attributed to prophylactic treatments for surgical site infection (SSI) after spinal surgery. SUMMARY OF BACKGROUND DATA: As a result of a rapidly increasing number of spinal procedures, health care expenditure is expected to increase substantially in the foreseeable future. Administration of effective prophylactic treatments may prevent occurrence of SSIs and may thus result in lower costs. To date, however, no review appraising the methodological quality of studies evaluating prophylactic treatments for spinal SSIs has been published. METHODS: Contemporary studies evaluating the preventive effect of prophylactic interventions on the rate of SSI after spinal surgery were searched through the Medline and EMBASE databases (January 2001 to December 2010). References were retrieved and bias-prone study features were abstracted individually and independently by 2 authors. RESULTS: Eighteen eligible studies were identified, including 6 randomized controlled trials and 12 comparative cohort studies. Most often, antibiotic prophylaxis administration was investigated (n = 7). Included studies covered a wide variation of indications and surgical procedures. Except for 5 studies (28%), applied definitions of SSI outcomes were ambiguous. Although several important methodological aspects, including blinding of outcome assessors and attrition, were poorly reported in randomized controlled trials, these studies were far less susceptible to bias and confounding as observed in nonrandomized studies. None of the 12 cohort studies adjusted for confounding by matching, stratification, or multivariate regression techniques. CONCLUSION: Given the plethora of previously hypothesized confounding risk factors for a spinal SSI, conduct of nonrandomized comparative therapeutic studies is strongly discouraged. On the other hand, methodological safeguards, including use of standardized definitions of putative confounders and outcomes, should be considered in more detail during the design phase of a randomized trial.

A methodological systematic review on surgical site infections following spinal surgery: part 1: risk factors.

STUDY DESIGN: A methodological systematic review. OBJECTIVE: To critically appraise the validity of risk factors for surgical site infection (SSI) after spinal surgery. SUMMARY OF BACKGROUND DATA: SSIs lead to higher morbidity, mortality, and increased health care costs. Understanding which factors lead to an increased risk of SSI is important for the development of prophylactic protocols to counter this risk. To date, however, no review appraising the methodological quality of studies evaluating risk factors for spinal SSIs has been published. METHODS: Contemporary studies identifying risk factors for SSI after spinal surgery were searched through the Medline and EMBASE databases (January 2001 to December 2010). References were retrieved and bias-prone study features were abstracted individually and independently by 2 authors. RESULTS: Twenty-four eligible studies were identified, including 9 (nested) case-control studies and 15 case series. Included studies covered wide variations of indications and surgical procedures. A total of 73 different types of factors were evaluated for the risk of an SSI of which 34 (47%) were reported to be significantly related to at least 1 study. Only the following risk factors-diabetes mellitus, obesity, and previous SSI-were confirmed more often (n = 11, 8, and 3, respectively) as a significant risk factor for an SSI than they were disproved (n = 7, 6, and 1, respectively). Various sources of heterogeneity were observed, including patient selection, selection and analysis of putative risk factors, and definitions of SSI outcomes. CONCLUSION: There is an abundance of conflicting data on risk factors for SSI after spinal surgery. Given various sources of heterogeneity observed in observational literature, there is a paucity of solid evidence for the proof of robust risk factors. The authors recommend the introduction, validation, and use of a standardized set of strongly justified eligibility criteria and well-defined candidate risk factors and spinal SSI outcomes.

A clinical prediction rule for ambulation outcomes after traumatic spinal cord injury: a longitudinal cohort study.

BACKGROUND: Traumatic spinal cord injury is a serious disorder in which early prediction of ambulation is important to counsel patients and to plan rehabilitation. We developed a reliable, validated prediction rule to assess a patient's chances of walking independently after such injury. METHODS: We undertook a longitudinal cohort study of adult patients with traumatic spinal cord injury, with early (within the first 15 days after injury) and late (1-year follow-up) clinical examinations, who were admitted to one of 19 European centres between July, 2001, and June, 2008. A clinical prediction rule based on age and neurological variables was derived from the international standards for neurological classification of spinal cord injury with a multivariate logistic regression model. Primary outcome measure 1 year after injury was independent indoor walking based on the Spinal Cord Independence Measure. Model performances were quantified with respect to discrimination (area under receiver-operating-characteristics curve [AUC]). Temporal validation was done in a second group of patients from July, 2008, to December, 2009. FINDINGS: Of 1442 patients with spinal cord injury, 492 had available outcome measures. A combination of age (<65 vs ≥65 years), motor scores of the quadriceps femoris (L3), gastrocsoleus (S1) muscles, and light touch sensation of dermatomes L3 and S1 showed excellent discrimination in distinguishing independent walkers from dependent walkers and non-walkers (AUC 0·956, 95% CI 0·936-0·976, p<0·0001). Temporal validation in 99 patients confirmed excellent discriminating ability of the prediction rule (AUC 0·967, 0·939-0·995, p<0·0001). INTERPRETATION: Our prediction rule, including age and four neurological tests, can give an early prognosis of an individual's ability to walk after traumatic spinal cord injury, which can be used to set rehabilitation goals and might improve the ability to stratify patients in interventional trials. FUNDING: Internationale Stiftung für Forschung in Paraplegie.

Diagnosis and prognosis of traumatic spinal cord injury.

Despite promising advances in basic spinal cord repair research, no effective therapy resulting in major neurological or functional recovery after traumatic spinal cord injury (tSCI) is available to date. The neurological examination according to the International Standards for Neurological and Functional Classification of Spinal Cord Injury Patients (International Standards) has become the cornerstone in the assessment of the severity and level of the injury. Based on parameters from the International Standards, physicians are able to inform patients about the predicted long-term outcomes, including the ability to walk, with high accuracy. In those patients who cannot participate in a reliable physical neurological examination, magnetic resonance imaging and electrophysiological examinations may provide useful diagnostic and prognostic information. As clinical research on this topic continues, the prognostic value of the reviewed diagnostic assessments will become more accurate in the near future. These advances will provide useful information for physicians to counsel tSCI patients and their families during the catastrophic initial phase after the injury.

The Edwin Smith papyrus: a clinical reappraisal of the oldest known document on spinal injuries.

Dating from the seventeenth century B.C: . the Edwin Smith papyrus is a unique treatise containing the oldest known descriptions of signs and symptoms of injuries of the spinal column and spinal cord. Based on a recent "medically based translation" of the Smith papyrus, its enclosed treasures in diagnostic, prognostic and therapeutic reasoning are revisited. Although patient demographics, diagnostic techniques and therapeutic options considerably changed over time, the documented rationale on spinal injuries can still be regarded as the state-of-the-art reasoning for modern clinical practice.

Isolated transverse process fractures of the subaxial cervical spine: a clinically insignificant injury or not?: a prospective, longitudinal analysis in a consecutive high-energy blunt trauma population.

STUDY DESIGN: Prospective single cohort study. OBJECTIVE: To analyze the incidence, associated injuries, treatment outcomes and associated adverse events of isolated transverse process fractures (TPFs) of the subaxial cervical spine in a high-energy blunt trauma population. SUMMARY OF BACKGROUND DATA: Currently, TPFs of the subaxial cervical spine are considered to be clinically insignificant. However, this hypothesis is based on clinical experience and has never been supported by research previously. METHODS: During a 32-month period, routine computed tomography scans of the spine were obtained in high-energy blunt trauma patients. Patients with isolated TPFs of the subaxial cervical spine were prospectively identified. For each enrolled patient, gender, age, mechanism of injury, trauma severity, neurologic deficit, injury levels, affected structures, treatment, radiographic follow-up, functional outcome (Cybex goniometer, neck disability index), and patient satisfaction (10 point visual analog scale) were recorded. RESULTS: Of 865 enrolled patients, 21 patients (2.4%) had 25 isolated TPFs of the subaxial cervical spine. The seventh vertebra was involved predominantly (76%). The initial treatment regimen was unrestricted movement in all patients. No associated adverse events were observed. A follow-up of 13 to 39 months was available in 14 patients. Follow-up showed a stable and intact subaxial cervical spine in all patients' radiographs, a patient satisfaction of 9.3 (SD 1.48), a Cybex measured range of motion in the sagittal plane of 109 degrees (SD 12.5, 95-129), the frontal plane of 70 (SD 17.8, 37-100) and the transverse plane of 144 (SD 12.5, 116-164), and a mean neck disability index score of 3.93 (SD 8.24). CONCLUSION: The incidence of isolated TPFs of the subaxial cervical spine was 2.4%. Unrestricted movement resulted in satisfying functional, anatomic, and neurologic outcomes without associated adverse events. This study confirms that isolated TPFs of the subaxial cervical spine can be considered as clinically insignificant and do not require treatment.

What should an ideal spinal injury classification system consist of? A methodological review and conceptual proposal for future classifications.

Since Böhler published the first categorization of spinal injuries based on plain radiographic examinations in 1929, numerous classifications have been proposed. Despite all these efforts, however, only a few have been tested for reliability and validity. This methodological, conceptual review summarizes that a spinal injury classification system should be clinically relevant, reliable and accurate. The clinical relevance of a classification is directly related to its content validity. The ideal content of a spinal injury classification should only include injury characteristics of the vertebral column, is primarily based on the increasingly routinely performed CT imaging, and is clearly distinctive from severity scales and treatment algorithms. Clearly defined observation and conversion criteria are crucial determinants of classification systems' reliability and accuracy. Ideally, two principle spinal injury characteristics should be easy to discern on diagnostic images: the specific location and morphology of the injured spinal structure. Given the current evidence and diagnostic imaging technology, descriptions of the mechanisms of injury and ligamentous injury should not be included in a spinal injury classification. The presence of concomitant neurologic deficits can be integrated in a spinal injury severity scale, which in turn can be considered in a spinal injury treatment algorithm. Ideally, a validation pathway of a spinal injury classification system should be completed prior to its clinical and scientific implementation. This review provides a methodological concept which might be considered prior to the synthesis of new or modified spinal injury classifications.