1.Abstract1.1.IntroductionSpinal Cord Injury (SCI) is a major cause of disability, with complications post-injury often leading to life-long health issues with need of extensive treatment. Neurological outcome post-SCI can be variable and difficult to predict, particularly in incomplete injured patients. The identification of specific SCI biomarkers in blood, may be able to improve prognostics in the field. This study has utilised proteomic and bioinformatics methodologies to investigate differentially expressed proteins in plasma samples across human SCI cohorts with the aim of identifying prognostic biomarkers and biological pathway alterations that relate to neurological outcome.1.2.Methods and MaterialsBlood samples were taken, following informed consent, from ASIA impairment scale (AIS) grade C “Improvers” (those who experienced an AIS grade improvement) and “Non-Improvers” (No AIS change), and AIS grade A and D at <2 weeks (“Acute”) and approx. 3 months (“Sub-acute”) post-injury. The total protein concentration from each sample was extracted, with pooled samples being labelled and non-pooled samples treated with ProteoMiner™ beads. Samples were then analysed using two 4-plex isobaric tag for relative and absolute quantification (iTRAQ) analyses and a label-free experiment for comparison, before quantifying with mass spectrometry. Data are available via ProteomeXchange with identifiers PXD035025 and PXD035072 for the iTRAQ and label-free experiments respectively.Proteomic datasets were analysed using OpenMS (version 2.6.0). R (version 4.1.4) and in particular, the R packages MSstats (version 4.0.1) and pathview (version 1.32.0) were used for downstream analysis. Proteins of interest identified from this analysis were further validated by enzyme-linked immunosorbent assay (ELISA).1.3.ResultsThe data demonstrated proteomic differences between the cohorts, with the results from the iTRAQ approach supporting those of the label-free analysis. A total of 79 and 87 differentially abundant proteins across AIS and longitudinal groups were identified from the iTRAQ and label-free analyses, respectively. Alpha-2-macroglobulin (A2M), retinol binding protein 4 (RBP4), serum amyloid A1 (SAA1), Peroxiredoxin 2, Apolipoprotein A1 (ApoA1) and several immunoglobulins were identified as bio-logically relevant and differentially abundant, with potential as individual prognostic biomarkers of neurological outcome. Bioinformatics analyses revealed that the majority of differentially abundant proteins were components of the complement cascade and most interacted directly with the liver.1.4.ConclusionsMany of the proteins of interest identified using proteomics were detected only in a single group and therefore have potential as a binary (present or absent) biomarkers, RBP4 and PRX-2 in particular. Additional investigations into the chronology of these proteins, and their levels in other tissues (cerebrospinal fluid in particular) are needed to better understand the underlying pathophysiology, including any potentially modifiable targets. Pathway analysis highlighted the complement cascade as being significant across groups of differential functional recovery.

CONTEXT:The Spinal Cord Independence Measure is a comprehensive functional rating scale for individuals with spinal cord lesion (SCL). OBJECTIVE:To validate the scores of the three subscales of SCIM IV, the fourth version of SCIM, using advanced statistical methods. STUDY DESIGN:Multi-center cohort study. SETTING:Nineteen SCL units in 11 countries. METHODS:SCIM developers created SCIM IV following comments by experts, included more accurate definitions of scoring criteria in the SCIM IV form, and adjusted it to assess specific conditions or situations that the third version, SCIM III, does not address. Professional staff members assessed 648 SCL inpatients, using SCIM IV and SCIM III, at admission to rehabilitation, and at discharge. The authors examined the validity and reliability of SCIM IV subscale scores using Rasch analysis. RESULTS:The study included inpatients aged 16-87 years old. SCIM IV subscale scores fit the Rasch model. All item infit and most item outfit mean-square indices were below 1.4; statistically distinct strata of abilities were 2.6-6; most categories were properly ordered; item hierarchy was stable across most clinical subgroups and countries. In a few items, however, we found misfit or category threshold disordering. We found SCIM III and SCIM IV Rasch properties to be comparable. CONCLUSIONS:Rasch analysis suggests that the scores of each SCIM IV subscale are reliable and valid. This reinforces the justification for using SCIM IV in clinical practice and research.

Objective: To examine the fourth version of the Spinal Cord Independence Measure for reliability and validity. Design: Partly blinded comparison with the criterion standard Spinal Cord Independence Measure III, and between examiners and examinations. Setting: A multicultural cohort from 19 spinal cord injury units in 11 countries. Participants: A total of 648 patients with spinal cord injury. Intervention: Assessment with Spinal Cord Independence Measure (SCIM IV) and Spinal Cord Independence Measure (SCIM III) on admission to inpatient rehabilitation and before discharge. Main outcome measures: SCIM IV interrater reliability, internal consistency, correlation with and difference from SCIM III, and responsiveness. Results: Total agreement between examiners was above 80% on most SCIM IV tasks. All Kappa coefficients were above 0.70 and statistically significant (P<. 001). Pearson's coefficients of the correlation between the examiners were above 0.90, and intraclass correlation coefficients were above 0.90. Cronbach's alpha was above 0.96 for the entire SCIM IV, above 0.66 for the subscales, and usually decreased when an item was eliminated. Reliability values were lower for the subscale of respiration and sphincter management, and on admission than at discharge. SCIM IV and SCIM III mean values were very close, and the coefficients of Pearson correlation between them were 0.91-0.96 (P<. 001). The responsiveness of SCIM IV was not significantly different from that of SCIM III in most of the comparisons. Conclusions: The validity, reliability, and responsiveness of SCIM IV, which was adjusted to assess specific patient conditions or situations that SCIM III does not address, and which includes more accurate definitions of certain scoring criteria, are very good and quite similar to those of SCIM III. SCIM IV can be used for clinical and research trials, including international multi-center studies, and its group scores can be compared with those of SCIM III. (C) 2021 The American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Background and Aims: This study aimed to determine the incidence of deep-vein thrombosis (DVT) and pulmonary embolism (PE) among patients admitted acutely to a regional spinal injury center, following spinal trauma; to compare its occurrence between those with spinal cord injury (SCI) and those without; and to assess the effect of various factors such as age, gender, neurological impairment, and duration of prophylaxis on the incidence observed. Patients and Methods: We retrospectively reviewed the charts of 374 consecutive patients who sustained traumatic spinal injury and were admitted acutely to the Midlands Centre for Spinal Injuries, Oswestry (UK), over a 3-year period. A total of 159 patients had spinal trauma with SCI and 215 were neurologically intact. The majority of these patients were treated nonsurgically and received the same thromboprophylactic regimen started within a median of 2 days postinjury. The incidence of clinical VTE (DVT and PE) was determined and some risk factors were assessed. Ethical approval was obtained through the Audit Office Committee of the Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry. Results: Among the neurologically intact group, one patient developed clinical PE (0.5%). Out of 159 patients with SCI, 23 developed clinically evident VTE (14.5%), 15 had DVT (11.9%), 4 had PE (5%), and 4 had both DVT and PE. There was no fatality. Complete SCI lesions were associated with higher incidence of VTE compared to incomplete lesions, 17.6% and 11%, respectively (P < 0.001). There were two peaks of thromboembolic episodes: the first during the first 2 weeks after injury (30% of cases) and the second was after the 8th week postinjury (38% of cases). A higher incidence of VTE was recorded in males than females (14.3% and 7.9%, respectively). Aso, the incidence of VTE is slightly higher in the age group between 40 and 60 years, but these differences were not statistically significant. Conclusions: SCI is associated with high risk of venous thromboembolism, and the risk increases with the severity of cord insult. While spinal column injury is shown to be associated with much lower risk. The risk is reduced with strict adherence to thromboprophylactic regimen which we suggest to continue for at least 12 weeks for SCI patients.

A questionnaire was developed to evaluate patients’ perspective on research aimed at improving functions and overcoming complications associated with spinal cord injury (SCI). The first three sections were based on published and validated assessment tools. The final section was developed to assess participant perspectives on research for SCI. One thousand patients were approached, of which 159 participated. Fifty-eight percent of participants were satisfied with their ‘life as a whole’. Two factors could be generated that reflected the variance in the data regarding participants’ life with a SCI: “ Psychosocial and physical wellbeing ” and “ Independent living ”. The majority of participants stated they would be involved in research (86%) or clinical trials (77%). However, the likelihood of participation dropped when potential risks of the research/trials were explained. Which participants would be willing to participate in research could not be predicted based on the severity of their injury, their psychosocial and physical wellbeing or their independent living. Despite participant establishment of a life with SCI, our data indicates that individuals strive for improvements in function. Participant willingness to be included in research studies is noteworthy and scientists and clinicians are encouraged to involve more patients in all aspects of their research.

Study design Explanatory and mechanistic study. Objectives A better understanding of the ‘whole-body’ response following spinal cord injury (SCI) is needed to guide future research aimed at developing novel therapeutic interventions and identifying prognostic indicators for SCI. This study aimed to characterise the blood proteome following contusion or complete SCI compared to a sham injury in rat models. Setting United Kingdom. Methods Pooled blood samples from one and seven days after a contusion (serum; n = 5) or from 14 days and 112 days post-complete transection SCI (plasma; n = 8) and their sham-injured counterparts were subjected to independent iTRAQ nanoflow liquid chromatography tandem mass-spectrometry proteomic analyses. Pathway analyses of the proteins that were differentially abundant between SCI and their matched sham injured counterparts were completed to indicate biological pathways that may be changed in response to SCI. Results Eleven and 42 proteins were differentially abundant (≥±2.0 FC; p ≤ 0.05) between the contusion SCI and sham injured animals at 24 h and seven days post-injury, respectively. Seven and tweleve proteins were differentially abundant between complete and sham injured rats at 14 and 112 days post-injury, respectively. Acute-phase response signalling and Liver X Receptor/Retinoic X Receptor activation were identified as differentially regulated pathways in both models of SCI. Conclusions We have utilised longitudinal preclinical SCI models to provide an insight into the blood proteome changes that result following SCI and to highlight a number of biological pathways of interest for future studies.

Neurological outcomes following spinal cord injury (SCI) are currently difficult to predict. While the initial American Spinal Injury Association Impairment Scale (AIS) grade can give an estimate of outcome, the high remaining degree of uncertainty has stoked recent interest in biomarkers for SCI. This study aimed to assess the prognostic value of routinely measured blood biomarkers by developing prognostic models of AIS scores at discharge and 12 months post-injury. Routine blood and clinical data were collected from SCI patients (n = 417), and blood measures that had been assessed in less than 50% of patients were excluded. Outcome neurology was obtained from AIS and Spinal Cord Independence Measure III (SCIM-III) scores at discharge and 12 months post-injury, with motor (AIS) and sensory (AIS, touch and prick) abilities being assessed individually. Linear regression models with and without elastic net penalization were created for all outcome measures. Blood measures associated with liver function, such as alanine transaminase, were found to add value to predictions of SCIM-III at discharge and 12 months post-injury. Further, components of a total blood count, including hemoglobin, were found to add value to predictions of AIS motor and sensory scores at discharge and 12 months post-injury. These findings corroborate the results of our previous preliminary study and thus provide further evidence that routine blood measures can add prognostic value in SCI and that markers of liver function are of particular interest.

There is increasing interest in the identification of biomarkers that could predict neurological outcome following a spinal cord injury (SCI). Although initial American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade is a good indicator of neurological outcome, for the patient and clinicians, an element of uncertainty remains. This preliminary study aimed to assess the additive potential of routine blood analytes following principal component analysis (PCA) to develop prognostic models for neurological outcome following SCI. Routine blood and clinical data were collected from SCI patients (n = 82) and PCA used to reduce the number of blood analytes into related factors. Outcome neurology was obtained from AIS scores at 3 and 12 months post-injury, with motor (AIS and total including all myotomes) and sensory (AIS, touch and pain) abilities being assessed individually. Multiple regression models were created for all outcome measures. Blood analytes relating to "liver function" and "acute inflammation and liver function" factors were found to significantly increase prediction of neurological outcome at both 3 months (touch, pain, and AIS sensory) and at 1 year (pain, R2 increased by 0.025 and total motor, R2 increased by 0.016). For some models "liver function" and "acute inflammation and liver function" factors were both significantly predictive, with the greatest combined R2 improvement of 0.043 occurring for 3 month pain prediction. These preliminary findings support ongoing research into the use of routine blood analytes in the prediction of neurological outcome in SCI patients.

Background Concomitant traumatic brain injury with spinal cord injury is likely to worsen prognosis and increase hospital length of stay. This study assessed the duration of in-patient rehabilitation and outcome in patients with both traumatic brain injury and spinal cord injury. Methods Retrospective study of all patients with concomitant traumatic brain injury and spinal cord injury over a 3-year period who had 5 years of subsequent follow-up at the Midlands Centre for Spinal Injuries. Results Twenty-seven patients had concomitant injuries of which five had severe traumatic brain injury, nine had moderate traumatic brain injury and the remaining thirteen had mild traumatic brain injury with spinal cord injury of grades A–D; commonest mechanisms of injury were motor vehicle collision (55%) and falls (37%). Thirteen (48%) had tetraplegia and 14 (52%) had paraplegia. Mean functional independence measure score at admission was 52.1 and 103.4 at 5 years. Patients with mild traumatic brain injury gained a mean functional independence measure score of 67.1; the moderate and severe traumatic brain injury patients gained mean functional independence measure score of 60.1 and 69.2, respectively. The mean length of stay was 138.3, 139.4 and 153.4 days for mild, moderate and severe traumatic brain injury, respectively. Conclusion Hospital length of stay and patient’s functioning at 5 years were not affected by traumatic brain injury severity in this subgroup; however, functional independence measure on its own may not be very sensitive to cognitive deficits.

Background Spinal cord injuries are relatively uncommon in children and evidence about long-term outcomes is limited. This study was performed to determine the frequency of common long-term complications in patients sustaining spinal injury in childhood (0–18 years) and who were followed up at a single dedicated spinal injuries centre in the UK. Method A retrospective review of clinical records of all patients injured at or less than 18 years of age between 1971 and 1999. Complications studied were renal, bowel, musculoskeletal, pressure ulcers and post-traumatic syringomyelia. Long-term social outcomes of independence, employment and driving were also assessed. Results Of 69 individuals (47 males, 22 females) the median age at injury was 17 years (range 0–18 y); 68% were older than 13 years at injury and 74% had traumatic injuries. Patients had an average duration of 27 years (12–43 years) of spinal injury – half had a neurological level of T6 and above, 80% had paraplegia and 20% had quadriplegia. Discussion Patients with both complete and incomplete spinal cord injury have minimal neurological recovery. Managing medical complications is vital as only 11.5% had normal voiding and 10.6% had normal bowel function. The incidence of skin ulcers increases with duration of spinal cord injury and scoliosis is higher in the non-traumatic injury group. Spasticity is observed in 66.6% and post-traumatic syringomyelia in 11.7%. Long-term social outcomes are good with 75% patients able to do independent care, 46% could drive and 39% managed employment or higher education. Conclusions This study documents the long-term outcomes and complications of spinal cord injuries sustained in childhood. With initial active physiological conservative management of the majority of patients, patient education and ongoing support the majority of patients achieved long-term survival and led independent and productive lives.

Spinal injuries without neurological damage have little effects on respiratory function unless associated with injury to the chest wall. Early verticalisation or mobilisation of these patients is safe and likely to improve vital capacity. Spinal injury with cord damage has a profound effect on the mechanics of respiration and on respiratory function particularly in cervical cord injuries. Around 40% of spinal cord injuries occur in the cervical spine, a trend that is steadily increasing, with respiratory causes being responsible for death in over 20% of individuals. Loss of lung volumes and relative hypoxemia contribute to global hypoxaemia, exacerbating cord ischaemia in the acute period. Respiratory compromise results in the loss of muscle strength generation capacity and reduced lung volumes and in particular vital capacity, of up to 70%, ineffective cough and secretion clearance abilities; reductions in both lung and chest wall compliance and an additional oxygen cost of breathing due to changes in respiratory mechanics, with obstructive sleep apnoea evident in over 50% of acute tetraplegics. While some countries have specialist spinal centres to manage such catastrophic trauma with a demonstrable improvement in health outcomes attributed to their contribution, many individuals are initially admitted to local hospitals where healthcare professionals are less likely to fully appreciate the significant and continued vulnerabilities of such individuals. This article aims to provide a basic understanding of the causes and identification of the main principles of the respiratory management strategies required to maintain pulmonary health for cervical spinal cord injury patients during the initial and early post trauma phase.

The management of the traumatic spinal injury has remained controversial since the times of Charles Bell and Astley Cooper. Traumatic spinal injuries in 1920s and 1930s were non-operatively managed. Methods of reduction included hyperextension in the prone position on slings, frames or hammock, as described by Davis and Rogers or hanging (Bohler). Watson-Jones used the two-table method in 1931 and 1934. Dunlop and Parker hyper extended the broken spine in supine position. Magnus renounced methods of forceful reduction and accepted the spinal deformity.

Spinal cord injury service delivery in the UK has improved over the years. The modern concept of Spinal Cord Injury care commenced after the Second World War. Patients started to live longer after the improvement in the medical and nursing care which was delivered in Spinal Cord Injury Centres across the country. In the last five years, spinal cord injury care has seen major advances. The Spinal Cord Injury Strategy Board was established in 2010 which led to the development of the Spinal Injury Pathway, the Spinal Injury National database and the creation of the clinical reference group for Spinal Cord Injury. This led to improvement in the care of evidence-based management.

OBJECTIVE:The aim of the study was to look at the long-term effects of conservative management of odontoid peg fractures.METHODS:We reviewed 48 consecutive patients with type II (32) and 16 type III, odontoid peg fractures. The clinical & radiological outcomes were assessed over an average period of follow up of 8 years. Union rate was determined and we discussed several factors that may affect it. Patients were treated conservatively with an average period of bed rest of 4 weeks followed by bracing for an average of 9 weeks.RESULTS:Bony union was established in 25 of 32 (78%) type II fractures. Of 7 cases of no bony union 4 were stable probably with fibrous union. 3 remained unstable. In 13 of 16(83%) type III fractures bony union was established. 2 of the 3 with no bony union were considered stable.CONCLUSION:Osseous non-union was higher in patients with displacement of >5 mm, but there is no correlation between union and age, gender or angulation of the fracture in both types.

Spinal cord injury service delivery in the UK has improved over the years. The modern concept of Spinal Cord Injury care commenced after the Second World War. Patients started to live longer after the improvement in the medical and nursing care which was delivered in Spinal Cord Injury Centres across the country. In the last five years, spinal cord injury care has seen major advances. The Spinal Cord Injury Strategy Board was established in 2010 which led to the development of the Spinal Injury Pathway, the Spinal Injury National database and the creation of the clinical reference group for Spinal Cord Injury. This led to improvement in the care of evidence-based management.

Study design: Review study. Objectives: The identification of prognostic biomarkers of spinal cord injury (SCI) will help to assign SCI patients to the correct treatment and rehabilitation regimes. Further, the detection of biomarkers that predict permanent neurological outcome would aid in appropriate recruitment of patients into clinical trials. The objective of this review is to evaluate the current state-of-play in this developing field. Setting: Studies from multiple countries were included. Methods: We have completed a comprehensive review of studies that have investigated prognostic biomarkers in either the blood or cerebrospinal fluid (CSF) of animals and humans following SCI. Results: Targeted and unbiased approaches have identified several prognostic biomarkers in CSF and blood. These proteins associate with cellular damage following SCI and include components from neurons, oligodendrocytes and reactive astrocytes, that is, neurofilament proteins, glial fibrillary acidic protein, Tau and S100 calcium-binding protein β. Unbiased approaches have also identified microRNAs that are specific to SCI, as well as other cell damage-associated proteins. Conclusions: The discovery and validation of stable, specific, sensitive and reproducible biomarkers of SCI is a rapidly expanding field of research. So far, few studies have utilised unbiased approaches aimed at the discovery of biomarkers within the CSF or blood in this field; however, some targeted approaches have been successfully used. Several studies using various animal models and some with small human patient cohorts have begun to pinpoint biomarkers in the CSF and blood with putative prognostic value. An increased sample size will be required to validate these biomarkers in the heterogeneous clinical setting.

Background. A quadratic formula of the Spinal Cord Injury Ability Realization Measurement Index (SCI-ARMI) has previously been published. This formula was based on a model of Spinal Cord Independence Measure (SCIM95), the 95th percentile of the SCIM III values, which correspond with the American Spinal Injury Association Motor Scores (AMS) of SCI patients. Objective. To further develop the original formula. Setting. Spinal cord injury centers from 6 countries and the Statistical Laboratory, Tel-Aviv University, Israel. Methods. SCIM95 of 661 SCI patients was modeled, using a quantile regression with or without adjustment for age and gender, to calculate SCI-ARMI values. SCI-ARMI gain during rehabilitation and its correlations were examined. Results. A new quadratic SCIM95 model was created. This resembled the previously published model, which yielded similar SCIM95 values in all the countries, after adjustment for age and gender. Without this adjustment, however, only 86% of the non-Israeli SCIM III observations were lower than those SCIM95 values (P < .0001). Adding the variables age and gender to the new model affected the SCIM95 value significantly (P < .04). Adding country information did not add a significant effect (P > .1). SCI-ARMI gain was positive (38.8 ± 22 points, P < .0001) and correlated weakly with admission age and AMS. Conclusions. The original quadratic SCI-ARMI formula is valid for an international population after adjustment for age and gender. The new formula considers more factors that affect functional ability following SCI.

BACKGROUND CONTEXT:Spondyloarthropathy has been described radiographically in patients following paralysis from spinal cord trauma. Onset of these findings after cauda equina syndrome have not been reported previously. Furthermore, the magnetic resonance documentation of its early evolution has not been recorded.PURPOSE:We report a case of early-onset spondyloarthropathy shown by magnetic resonance imaging (MRI) in a patient with cauda equina syndrome due to bilateral sacral insufficiency fractures.STUDY DESIGN:Unique case study review, one case.METHODS:Review of the clinical case notes and imaging including initial and subsequent MR imaging.RESULTS:The initial MRI of the lumbosacral spine showed bilateral sacral insufficiency fractures with a kyphotic deformity. The vertebral bodies were normal on the initial computed tomography and MRI studies, which did not reveal pre-existing features of sacroiliitis. The second MRI performed 5 months later clearly showed spondylitis at multiple vertebral levels with partial resolution 18 months post injury.CONCLUSION:Spondyloarthropathy in patients with paralysis due to spinal cord injury is well documented in the English language literature, but until now this has not been demonstrated by MRI. It is a rare complication of traumatic cauda equina syndrome that commences soon after the traumatic event and can resolve spontaneously.

Transplantation of bone marrow stem cells into spinal cord lesions enhances axonal regeneration and promotes functional recovery in animal studies. There are two types of adult bone marrow stem cell; hematopoietic stem cells (HSCs), and mesenchymal stem cells (MSCs). The mechanisms by which HSCs and MSCs might promote spinal cord repair following transplantation have been extensively investigated. The objective of this review is to discuss these mechanisms; we briefly consider the controversial topic of HSC and MSC transdifferentiation into central nervous system cells but focus on the neurotrophic, tissue sparing, and reparative action of MSC grafts in the context of the spinal cord injury (SCI) milieu. We then discuss some of the specific issues related to the translation of HSC and MSC therapies for patients with SCI and present a comprehensive critique of the current bone marrow cell clinical trials for the treatment of SCI to date.