J.J. van Middendorp

Biomarkers in spinal cord injury

Study design:Literature review.Objectives:In traumatic spinal cord injury (SCI), much effort has been put into the evaluation of SCI severity and the prediction of recovery potential. An accurate prediction of the initial damage of the spinal cord that differentiates between the severities of SCI however, may help physicians in choosing a particular neuroprotective treatment in the acute phase. Neurochemical biomarkers may possibly fulfil these requirements. The aim of this review was to describe (1) the current status of neurochemical biomarkers in SCI; (2) their potential diagnostic role in SCI.Methods:MEDLINE was searched from 1966 to 2008 to identify publications concerning biomarkers in traumatic SCI.Results:The biomarkers S-100β, neuron-specific enolase, neurofilament light chain, and Glial fibrillary acidic protein are significantly increased in cases of (experimental) spinal cord injury. Furthermore, increased serum concentrations of S-100β have been correlated with an unfavourable functional outcome. Although biomarkers in SCI show promising results, considerations and shortcomings, such as polytrauma, haemolysis, extracerebral sources, and poor resuscitation, must be studied in greater detail before biomarkers can be utilised in the clinical care of SCI.Conclusions:Quantitative standards for determining the extent of SCI during the acute phase must be developed and validated. Even though increased concentrations of neurochemical biomarkers have been identified in patients with SCI, these do not yet provide a sensitive prognostic tool. Considering the limited availability of sensitive prognostic tools, neurochemical biomarkers of SCI should be evaluated and validated in future clinical trials.

ASIA impairment scale conversion in traumatic SCI: is it related with the ability to walk? A descriptive comparison with functional ambulation outcome measures in 273 patients.

Study design:Prospective multicenter longitudinal cohort study.Objectives:To determine the relationship between improvements of the American Spinal Injury Association/International Spinal Cord Society (ASIA/ISCoS) neurological standard scale (AIS) outcome measure and improvements of functional ambulatory outcome measures in patients with traumatic spinal cord injury (SCI).Setting:European multicenter study of human SCI (EM-SCI).Methods:In 273 eligible patients with traumatic SCI, acute (0–15 days) and chronic phase (6 or 12 months) AIS grades, timed up and go (TUG) test and 10-m walk test (10MWT) outcome measurements were analyzed. Subanalysis of those patients who did have AIS conversion was performed to assess its relation with functional ambulatory outcomes.Results:Studied population consisted of 161 acute phase AIS grade A patients; 37 grade B; 43 grade C and 32 acute phase AIS grade D patients. Forty-two patients (26%) converted from AIS grade A, 27 (73%) from grade B, 32 (75%) from grade C and five patients (16%) from AIS grade D. The frequencies of AIS conversions and functional ambulation recovery outcomes were significantly different (P<0.001) in patients with motor complete SCI. The ratio of patients with both recovery of ambulatory function and AIS conversion (n=101) differed significantly (P<0.001) between the acute phase AIS grade scores; AIS grade A (6/40 patients, 15%), B (9/27 patients, 33%), C (23/29 patients, 79%) and D (5/5 patients 100%).Conclusions:The AIS conversion outcome measure is poorly related to the ability to walk in traumatic SCI patients. Therefore, the authors recommend the use of functional ambulation recovery outcome measures in prognosticating the recovery of walking capacity and performance of patients with SCI.

Is determination between complete and incomplete traumatic spinal cord injury clinically relevant? Validation of the ASIA sacral sparing criteria in a prospective cohort of 432 patients.

Study design:Prospective multicenter longitudinal cohort study.Objective:To validate the prognostic value of the acute phase sacral sparing measurements with regard to chronic phase-independent ambulation in patients with traumatic spinal cord injury (SCI).Setting:European Multicenter Study of Human Spinal Cord Injury (EM-SCI).Methods:In 432 patients, acute phase (0–15 days) American Spinal Injury Association (ASIA)/International Spinal Cord Society neurological standard scale (AIS) grades, ASIA sacral sparing measurements, which are S4–5 light touch (LT), S4–5 pin prick (PP), anal sensation and voluntary anal contraction; and chronic phase (6 or 12 months) indoor mobility Spinal Cord Independence Measure (SCIM) measurements were analyzed. Calculations of positive and negative predictive values (PPV/NPV) as well as univariate and multivariate logistic regressions were performed in all four sacral sparing criteria. The area under the receiver-operating characteristic curve (AUC) ratios of all regression equations was calculated.Results:To achieve independent ambulation 1-year post injury, a normal S4–5 PP score showed the best PPV (96.5%, P<0.001, 95% confidence interval (95% CI): 87.9–99.6). Best NPV was reported in the S4–5 LT score (91.7%, P<0.001, 95% CI: 81.6–97.2). The use of the combination of only voluntary anal contraction and the S4–5 LT and PP sensory scores (AUC: 0.906, P<0.001, 95% CI: 0.871–0.941) showed significantly better (P<0.001, 95% CI: 0.038–0.128) discriminating results in prognosticating 1-year independent ambulation than with the use of currently used distinction between complete and incomplete SCI (AUC: 0.823, P<0.001, 95% CI: 0.781–0.864).Conclusions:Out of the four sacral sparing criteria, the acute phase anal sensory score measurements do not contribute significantly to the prognosis of independent ambulation. The combination of the acute phase voluntary anal contraction and the S4–5 LT and PP scores, predicts significantly better chronic phase-independent ambulation outcomes than the currently used distinction between complete and incomplete SCI.Sponsorship:This study was granted by ‘Acute Zorgregio Oost’ and the ‘Internationale Stiftung für Forschung in Paraplegie (IFP)’.

Diagnostic criteria of traumatic central cord syndrome. Part 1: a systematic review of clinical descriptors and scores.

Study design:Systematic review.Background:The applied definition of traumatic central cord syndrome (TCCS) lacks specific quantified diagnostic criteria.Objective:To review currently applied TCCS diagnostic criteria and quantitative data regarding the ‘disproportionate weakness’ between the upper and lower extremities described in original studies reporting on TCCS subjects.Methods:A MEDLINE (1966 to 2008) literature search was conducted. The descriptors applied to define TCCS were extracted from all included articles. We included original studies that reported on the differences in motor score (based on the Medical Research Council scale) between the total upper extremity motor score (UEMS) and the total lower extremity motor score (LEMS), in a minimum of five TCCS patients at the time of hospital admission. The mean difference between the total UEMS and the total LEMS of the patients included in each study was calculated. Case reports were excluded.Results:None of the identified studies on TCCS patients reported inclusion and/or exclusion criteria using a quantified difference between the UEMS and LEMS. Out of 30 retrieved studies, we identified seven different clinical descriptors that have been applied as TCCS diagnostic criteria. Nine studies reporting on a total of 312 TCCS patients were eligible for analysis. The mean total UEMS was 10.5 motor points lower than the mean total LEMS.Conclusions:There is no consensus on the diagnostic criteria for TCCS. Nevertheless, this review revealed an average of 10 motor points between the UEMS and LEMS as a possible TCCS diagnostic criterion. However, further discussion by an expert panel will be required to establish definitive diagnostic criteria.

Design and rationale of a Prospective, Observational European Multicenter study on the efficacy of acute surgical decompression after traumatic Spinal Cord Injury: the SCI-POEM study.

Objectives:Despite many years of research, there is currently no treatment available that results in major neurological or functional recovery after traumatic spinal cord injury (tSCI). In particular, no conclusive data related to the role of the timing of decompressive surgery, and the impact of injury severity on its benefit, have been published to date. This paper presents a protocol that was designed to examine the hypothesized association between the timing of surgical decompression and the extent of neurological recovery in tSCI patients.Study design:The SCI-POEM study is a Prospective, Observational European Multicenter comparative cohort study. This study compares acute (<12 h) versus non-acute (>12 h, <2 weeks) decompressive surgery in patients with a traumatic spinal column injury and concomitant spinal cord injury. The sample size calculation was based on a representative European patient cohort of 492 tSCI patients. During a 4-year period, 300 patients will need to be enrolled from 10 trauma centers across Europe. The primary endpoint is lower-extremity motor score as assessed according to the ‘International standards for neurological classification of SCI’ at 12 months after injury. Secondary endpoints include motor, sensory, imaging and functional outcomes at 3, 6 and 12 months after injury.Conclusion:In order to minimize bias and reduce the impact of confounders, special attention is paid to key methodological principles in this study protocol. A significant difference in safety and/or efficacy endpoints will provide meaningful information to clinicians, as this would confirm the hypothesis that rapid referral to and treatment in specialized centers result in important improvements in tSCI patients.

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.

Relevance of the diagnosis traumatic cervical Brown-Sequard-plus syndrome: an analysis based on the neurological and functional recovery in a prospective cohort of 148 patients.

Study design:Prospective multi-center cohort study.Objectives:To compare the neurological and functional recovery between tetraplegic Brown-Séquard-plus syndrome (BSPS) and incomplete tetraplegia (non-BSPS).Setting:European Multicenter Study of Human Spinal Cord Injury (EM-SCI).Methods:BSPS was defined as a traumatic incomplete spinal cord injury (SCI) with ipsilateral weakness and contralateral loss of pinprick sensation at neurologic levels C2–T1. Acute (0–15 days) and chronic phase (6 or 12 months) were assessed for the American Spinal Injury Association (ASIA) sensory scores, upper extremity motor scores and lower extremity motor scores. Furthermore, chronic phase scores of all Spinal Cord Independence Measure (SCIM) II items were analyzed. Differences in neurological and functional outcome between BSPS patients and non-BSPS patients were calculated using Students t-tests and Wilcoxon signed rank tests.Results:Out of 148 tetraplegic patients, 30 were diagnosed with BSPS. Patients with an ASIA impairment scale (AIS) B were significantly (P<0.001) more identified in non-BSPS patients (25%) compared with BSPS patients (3%), respectively. After 12 months, the median scores for sphincter management of the bladder for both BSPS and non-BSPS patients were 15. Both 25 and 75% quartile median scores were 15 for BSPS patients and 12 and 15 for non-BSPS patients (P<0.02). Except for the difference in bladder function, no significant differences were identified in other SCIM II subitems and ASIA motor or sensory scores between BSPS and non-BSPS patients when stratified for injury severity by excluding AIS B patients.Conclusion:Compared with incomplete tetraplegic patients, patients with cervical BSPS have a similar neurological and functional recovery when matched for the AIS.

Diagnostic criteria of traumatic central cord syndrome. Part 3: Descriptive analyses of neurological and functional outcomes in a prospective cohort of traumatic motor incomplete tetraplegics

Study design:Prospective multicenter cohort study.Objectives:To compare the neurological recovery and functional outcomes between traumatic central cord syndrome (TCCS) patients and motor incomplete tetraplegic patients.Setting:European Multicenter Study of human spinal cord injury.Methods:In 248 traumatic motor incomplete tetraplegics, initial phase (0–15 days) American Spinal Injury Association (ASIA) impairment grading, upper and lower extremity motor scores (UEMS and LEMS), upper and lower sensory scores and chronic phase (6 or 12 months) neurological outcomes were analyzed. In addition, chronic phase self-care and indoor mobility Spinal Cord Independence Measure (SCIM) items were studied. Tetraplegics were subdivided into three groups: (1) non-TCCS group (UEMS⩾LEMS), (2) intermediate-TCCS group (UEMS=(1–9 points)<LEMS) and (3) TCCS group (UEMS=(⩾10 points)<LEMS). Students t-tests and χ2-tests were applied.Results:A total of 89 non-TCCS subjects (AIS D, n=28), 62 int-TCCS (AIS D, n=43) and 97 TCCS (AIS D, n=80) subjects were analysed. Although minimal significant differences in chronic phase LEMS and UEMS outcomes were identified between TCCS and non-TCCS patients after stratification by the AIS grade, our data showed no significant differences in functional upper and lower extremity outcomes at 6 or 12 months post-injury.Conclusion:The AIS grading system, and not the diagnosis TCCS, continues to be the best available prognostic parameter for neurological and functional outcomes in motor incomplete tetraplegics. The authors recommend that for future outcome studies in motor incomplete tetraplegia, patients should not be selected based on, or stratified by, the diagnosis TCCS.

Top ten research priorities for spinal cord injury: the methodology and results of a British priority setting partnership

Study design:This is a mixed-method consensus development project.Objectives:The objective of this study was to identify a top ten list of priorities for future research into spinal cord injury (SCI).Setting:The British Spinal Cord Injury Priority Setting Partnership was established in 2013 and completed in 2014. Stakeholders included consumer organisations, healthcare professional societies and caregivers.Methods:This partnership involved the following four key stages: (i) gathering of research questions, (ii) checking of existing research evidence, (iii) interim prioritisation and (iv) a final consensus meeting to reach agreement on the top ten research priorities. Adult individuals with spinal cord dysfunction because of trauma or non-traumatic causes, including transverse myelitis, and individuals with a cauda equina syndrome (henceforth grouped and referred to as SCI) were invited to participate in this priority setting partnership.Results:We collected 784 questions from 403 survey respondents (290 individuals with SCI), which, after merging duplicate questions and checking systematic reviews for evidence, were reduced to 109 unique unanswered research questions. A total of 293 people (211 individuals with SCI) participated in the interim prioritisation process, leading to the identification of 25 priorities. At a final consensus meeting, a representative group of individuals with SCI, caregivers and health professionals agreed on their top ten research priorities.Conclusion:Following a comprehensive, rigorous and inclusive process, with participation from individuals with SCI, caregivers and health professionals, the SCI research agenda has been defined by people to whom it matters most and should inform the scope and future activities of funders and researchers for the years to come.Sponsorship:The NIHR Oxford Biomedical Research Centre provided core funding for this project.

Pre-hospital and acute management of traumatic spinal cord injury in the Netherlands: survey results urge the need for standardisation

Study design:Questionnaire survey.Objectives:Although a range of novel therapeutic approaches for traumatic spinal cord injury (tSCI) are being trialled in highly standardised, pre-clinical research models, little has been published about the extent of standardisation in health service delivery for newly injured tSCI patients.Setting:All Emergency Medical Services (EMSs) and 11 level-1 trauma centres (L1TCs) in the Netherlands.Methods:A survey assessing the organisation of pre-hospital and acute tSCI management was developed and distributed across all 23 pre-hospital EMSs and 11 L1TCs based in the Netherlands.Results:Response rates for EMSs and L1TCs were 82 and 100%, respectively. Thirteen EMSs (68%) transported all patients who are suspected of having tSCI to L1TCs. The decision to transfer tSCI patients to L1TCs was primarily made by paramedics at the scene of accident (79%). Nonetheless, no EMS reported the use of validated neurological assessments for determining the likelihood of tSCI. The International Standards for Neurological Classification of SCI were used to determine the level and severity of tSCI in four centres, and three centres performed magnetic resonance imaging in all tSCI patients. Three L1TCs had spinal cord perfusion support protocols in place, and two centres administered methylprednisolon to acute tSCI patients.Conclusion:We found a large variance in the delivery of pre-hospital and acute tSCI management in a well-defined geographical catchment area. This survey urges the need for implementing standardised assessments and developing best-practice guidelines, which should be endorsed by all pre-hospital and acute tSCI health-care providers.