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Purpose: Mobility impairments are a common consequence of stroke and spinal cord injury (SCI). Assistive products (APs) such as wheelchairs are often needed for activities and participation. The aim of the study was to explore the provision and use of APs in Germany and to identify associated factors underlying this practice., Materials and Methods: Semi-structured interviews were conducted with 19 professionals from outpatient neurorehabilitation services (three general practitioners, five physical therapists, five occupational therapists, one speech therapist, one neuropsychologist, two outpatient nurses, one rehab technician and one social worker), two patient advocates (long-term survivors, each stroke and SCI) and 20 patients (10 each after stroke and SCI with mobility impairment, and first-ever affected). Analysis was performed by qualitative content analysis., Results: Reported experiences were mixed, varying from high satisfaction to unusable APs and unmet needs. Identified factors associated with these experiences were related to care pathways, care coordination, inter-professional collaboration, professionals' knowledge and patient information, cost coverage, and approval procedures., Conclusion: Overall, patients seem satisfied with the APs they receive, but patients with more severe mobility impairments in particular experience deficits in the provision and use of APs. Further research is needed to develop and test strategies for the provision and use of APs.

Background and Objectives: Neurological and functional recovery after traumatic spinal cord injury (SCI) is highly challenged by the level of the lesion and the high heterogeneity in severity (different degrees of in/complete SCI) and spinal cord syndromes (hemi-, ant-, central-, and posterior cord). So far outcome predictions in clinical trials are limited in targeting sum motor scores of the upper (UEMS) and lower limb (LEMS) while neglecting that the distribution of motor function is essential for functional outcomes. The development of data-driven prediction models of detailed segmental motor recovery for all spinal segments from the level of lesion towards the lowest motor segments will improve the design of rehabilitation programs and the sensitivity of clinical trials., Methods: This study used acute-phase International Standards for Neurological Classification of SCI exams to forecast 6-month recovery of segmental motor scores as the primary evaluation endpoint. Secondary endpoints included severity grade improvement, independent walking, and self-care ability. Different similarity metrics were explored for k-nearest neighbor (kNN) matching within 1267 patients from the European Multicenter Study about Spinal Cord Injury before validation in 411 patients from the Sygen trial. The kNN performance was compared to linear and logistic regression models., Results: We obtained a population-wide root-mean-squared error (RMSE) in motor score sequence of 0.76(0.14, 2.77) and competitive functional score predictions (AUC walker  = 0.92, AUC self-carer  = 0.83) for the kNN algorithm, improving beyond the linear regression task (RMSE linear  = 0.98(0.22, 2.57)). The validation cohort showed comparable results (RMSE = 0.75(0.13, 2.57), AUC walker  = 0.92). We deploy the final historic control model as a web tool for easy user interaction (https://hicsci.ethz.ch/)., Discussion: Our approach is the first to provide predictions across all motor segments independent of the level and severity of SCI. We provide a machine learning concept that is highly interpretable, i.e. the prediction formation process is transparent, that has been validated across European and American data sets, and provides reliable and validated algorithms to incorporate external control data to increase sensitivity and feasibility of multinational clinical trials., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: When mobility deficits persist after stroke or spinal cord injury (SCI), outpatient neurorehabilitation services are required. This study aimed to explore the current practice of German outpatient neurorehabilitation services and identify factors associated to this practice., Methods: This was a qualitative observational study in which semi-structured interviews were conducted with professionals from outpatient neurorehabilitation services and mobility-impaired patients. A qualitative content analysis with a data-driven coding process was used., Results: Three general practitioners, five physical, five occupational, and one speech therapist, one neuropsychologist, two outpatient nurses, one rehabilitation technician, one social worker, two patient advocates (long-term survivors, each stroke and SCI), and 20 patients (10 after stroke, 10 after SCI, all first-ever affected since approximately one year) participated. The reported experiences ranged from high satisfaction to perceived deficits in participation-oriented, evidence-based, and coordinated care. Identified associated factors were: (a) availability of specialised therapists and professional education, (b) outpatient service catalogue, (c) cost coverage, (d) setting rehabilitation goals, and (e) physician as care coordinator., Conclusion: Areas of improvement identified focused on: setting rehabilitation goals towards participation, training therapists on evidence-based treatments and shared decision-making, updating the outpatient service catalogue, and implementing coordination actions. Implementation of these recommendations should be evaluated.

Abstract: Evidence from previous studies supports the concept that spinal cord injury (SCI)-induced neuropathic pain (NP) has its neural roots in the peripheral nervous system. There is uncertainty about how and to which degree mechanoreceptors contribute. Sensorimotor activation-based interventions (eg, treadmill training) have been shown to reduce NP after experimental SCI, suggesting transmission of pain-alleviating signals through mechanoreceptors. The aim of the present study was to understand the contribution of mechanoreceptors with respect to mechanical allodynia in a moderate mouse contusion SCI model. After genetic ablation of tropomyosin receptor kinase B expressing mechanoreceptors before SCI, mechanical allodynia was reduced. The identical genetic ablation after SCI did not yield any change in pain behavior. Peptidergic nociceptor sprouting into lamina III/IV below injury level as a consequence of SCI was not altered by either mechanoreceptor ablation. However, skin-nerve preparations of contusion SCI mice 7 days after injury yielded hyperexcitability in nociceptors, not in mechanoreceptors, which makes a substantial direct contribution of mechanoreceptors to NP maintenance unlikely. Complementing animal data, quantitative sensory testing in human SCI subjects indicated reduced mechanical pain thresholds, whereas the mechanical detection threshold was not altered. Taken together, early mechanoreceptor ablation modulates pain behavior, most likely through indirect mechanisms. Hyperexcitable nociceptors seem to be the main drivers of SCI-induced NP. Future studies need to focus on injury-derived factors triggering early-onset nociceptor hyperexcitability, which could serve as targets for more effective therapeutic interventions., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Background and Purpose: It is unknown whether changes to the peripheral nervous system following spinal cord injury (SCI) are relevant for functional recovery or the development of neuropathic pain below the level of injury. Magnetic resonance neurography (MRN) at 3 T allows detection and localization of structural and functional nerve damage. This study aimed to combine MRN and clinical assessments in individuals with chronic SCI and nondisabled controls., Methods: Twenty participants with chronic SCI and 20 controls matched for gender, age, and body mass index underwent MRN of the L5 dorsal root ganglia (DRG) and the sciatic nerve. DRG volume, sciatic nerve mean cross-sectional area (CSA), fascicular lesion load, and fractional anisotropy (FA), a marker for functional nerve integrity, were calculated. Results were correlated with clinical assessments and nerve conduction studies., Results: Sciatic nerve CSA and lesion load were higher (21.29 ± 5.82 mm 2 vs. 14.08 ± 4.62 mm 2 , p < 0.001; and 8.70 ± 7.47% vs. 3.60 ± 2.45%, p < 0.001) in individuals with SCI compared to controls, whereas FA was lower (0.55 ± 0.11 vs. 0.63 ± 0.08, p = 0.022). DRG volumes were larger in individuals with SCI who suffered from neuropathic pain compared to those without neuropathic pain (223.7 ± 53.08 mm 3 vs. 159.7 ± 55.66 mm 3 , p = 0.043). Sciatic MRN parameters correlated with electrophysiological results but did not correlate with the extent of myelopathy or clinical severity of SCI., Conclusions: Individuals with chronic SCI are subject to a decline of structural peripheral nerve integrity that may occur independently from the clinical severity of SCI. Larger volumes of DRG in SCI with neuropathic pain support existing evidence from animal studies on SCI-related neuropathic pain., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: To use the ulnar compound muscle action potential (CMAP) to abductor digiti minimi (ADM) to identify the proportion of individuals with cervical spinal cord injury (SCI) who have lower motor neuron (LMN) abnormalities involving the C8-T1 spinal nerve roots, within 3-6 months, and thus may influence the response to nerve transfer surgery., Design: Retrospective analysis of prospectively collected data. Data were analyzed from European Multicenter Study About SCI database., Setting: Multi-center, academic hospitals., Participants: We included 79 subjects (age=41.4±17.7, range:16-75; 59 men; N=79), who were classified as cervical level injuries 2 weeks after injury and who had manual muscle strength examinations that would warrant consideration for nerve transfer (C5≥4, C8<3)., Interventions: None., Main Outcome Measures: The ulnar nerve CMAP amplitude to ADM was used as a proxy measure for C8-T1 spinal segment health. CMAP amplitude was stratified into very abnormal (<1.0 mV), sub-normal (1.0-5.9 mV), and normal (>6.0 mV). Analysis took place at 3 (n=148 limbs) and 6 months (n=145 limbs)., Results: At 3- and 6-month post-injury, 33.1% and 28.3% of limbs had very abnormal CMAP amplitudes, respectively, while in 54.1% and 51.7%, CMAPs were sub-normal. Median change in amplitude from 3 to 6 months was 0.0 mV for very abnormal and 1.0 mV for subnormal groups. A 3-month ulnar CMAP <1 mV had a positive predictive value of 0.73 (95% CI 0.69-0.76) and 0.78 (95% CI 0.75-0.80) for C8 and T1 muscle strength of 0 vs 1 or 2., Conclusion: A high proportion of individuals have ulnar CMAPs below the lower limit of normal 3- and 6-month post cervical SCI and may also have intercurrent LMN injury. Failure to identify individuals with LMN denervation could result in a lost opportunity to improve hand function through timely nerve transfer surgeries., (Copyright © 2023 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Locomotion is a complex task involving excitatory and inhibitory circuitry in spinal gray matter. While genetic knockouts examine the function of individual spinal interneuron (SpIN) subtypes, the phenotype of combined SpIN loss remains to be explored. We modified a kainic acid lesion to damage intermediate gray matter (laminae V-VIII) in the lumbar spinal enlargement (spinal L2-L4) in female rats. A thorough, tailored behavioral evaluation revealed deficits in gross hindlimb function, skilled walking, coordination, balance and gait two weeks post-injury. Using a Random Forest algorithm, we combined these behavioral assessments into a highly predictive binary classification system that strongly correlated with structural deficits in the rostro-caudal axis. Machine-learning quantification confirmed interneuronal damage to laminae V-VIII in spinal L2-L4 correlates with hindlimb dysfunction. White matter alterations and lower motoneuron loss were not observed with this KA lesion. Animals did not regain lost sensorimotor function three months after injury, indicating that natural recovery mechanisms of the spinal cord cannot compensate for loss of laminae V-VIII neurons. As gray matter damage accounts for neurological/walking dysfunction in instances of spinal cord injury affecting the cervical or lumbar enlargement, this research lays the groundwork for new neuroregenerative therapies to replace these lost neuronal pools vital to sensorimotor function., Competing Interests: The authors declare that they have no conflict of interest., (Copyright: © 2023 Kuehn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: There are approximately 140 000 people in Germany with spinal cord injury, with approximately 2400 new patients each year. Cervical spinal cord injuries cause, to varying degrees, weakness and impairment of everyday activities of the limbs (tetraparesis, tetraplegia)., Methods: This review is based on relevant publications retrieved by a selective search of the literature., Results: From among 330 initially screened publications, 40 were included and analyzed. Muscle and tendon transfers, tenodeses, and joint stabilizations yielded reliable functional improvement of the upper limb. Tendon transfers improved the strength of elbow extension from M0 to an average of M3.3 (BMRC) and grip strength to approximately 2 kg. In the long term, 17-20% of strength is lost after active tendon transfers and slightly more after passive ones. Nerve transfers improved strength to M3 or M4 in over 80% of cases, with the best results overall in patients under 25 years of age who underwent early surgery (within 6 months of the accident). Combined procedures in a single operation have been found to be advantageous compared to the traditional multistep approach. Nerve transfers from intact fascicles at segmental levels above that of the spinal cord lesion have been found to be a valuable addition to the established varieties of muscle and tendon transfer. The reported long-term patient satisfaction is generally high., Conclusion: Modern techniques of hand surgery can help suitably selected tetraparetic and tetraplegic patients regain the use of their upper limbs. Competent interdisciplinary counseling about these surgical options should be offered as early as possible to all affected persons as an integral part of their treatment plan.

Paresis after spinal cord injury (SCI) is caused by damage to upper and lower motoneurons (LMNs) and may differentially impact neurological recovery. This prospective monocentric longitudinal observational study investigated the extent and severity of LMN dysfunction and its impact on upper extremity motor recovery after acute cervical SCI. Pathological spontaneous activity at rest and/or increased discharge rates of motor unit action potentials recorded by needle electromyography (EMG) were taken as parameters for LMN dysfunction and its relation to the extent of myelopathy in the first available spine magnetic resonance imaging (MRI) was determined. Motor recovery was assessed by standardized neurological examination within the first four weeks (acute stage) and up to one year (chronic stage) after injury. Eighty-five muscles of 17 individuals with cervical SCI (neurological level of injury from C1 to C7) and a median age of 54 (28-59) years were examined. The results showed that muscles with signs of LMN dysfunction peaked at the lesion center (Χ 2 [2, n  = 85] = 6.6, p  = 0.04) and that the severity of LMN dysfunction correlated with T2-weighted hyperintense MRI signal changes in routine spine MRI at the lesion site (Spearman ρ = 0.31, p  = 0.01). Muscles exhibiting signs of LMN dysfunction, as indicated by pathological spontaneous activity at rest and/or increased discharge rates of motor unit action potentials, were associated with more severe paresis in both the acute and chronic stages after SCI (Spearman ρ acute = -0.22, p  = 0.04 and chronic = -0.31, p  = 0.004). Moreover, the severity of LMN dysfunction in the acute stage was also associated with a greater degree of paresis (Spearman ρ acute = -0.24, p  = 0.03 and chronic = -0.35, p  = 0.001). While both muscles with and without signs of LMN dysfunction were capable of regaining strength over time, those without LMN dysfunctions had a higher potential to reach full strength. Muscles with signs of LMN dysfunction in the acute stage displayed increased amplitudes of motor unit action potentials with chronic-stage needle EMG, indicating reinnervation through peripheral collateral sprouting as compensatory mechanism (Χ 2 [1, n  = 72] = 4.3, p  = 0.04). Thus, LMN dysfunction represents a relevant factor contributing to motor impairment and recovery in acute cervical SCI. Defined recovery mechanisms (peripheral reinnervation) may at least partially underlie spontaneous recovery in respective muscles. Therefore, assessment of LMN dysfunction could help refine prediction of motor recovery after SCI.

Background: Accurate prediction of walking function after a traumatic spinal cord injury (SCI) is crucial for an appropriate tailoring and application of therapeutical interventions. Long-term outcome of ambulation is strongly related to residual muscle function acutely after injury and its recovery potential. The identification of the underlying determinants of ambulation, however, remains a challenging task in SCI, a neurological disorder presented with heterogeneous clinical manifestations and recovery trajectories., Objectives: Stratification of walking function and determination of its most relevant underlying muscle functions based on stratified homogeneous patient subgroups., Methods: Data from individuals with paraplegic SCI were used to develop a prediction-based stratification model, applying unbiased recursive partitioning conditional inference tree (URP-CTREE). The primary outcome was the 6-minute walk test at 6 months after injury. Standardized neurological assessments ≤15 days after injury were chosen as predictors. Resulting subgroups were incorporated into a subsequent node-specific analysis to attribute the role of individual lower extremity myotomes for the prognosis of walking function., Results: Using URP-CTREE, the study group of 361 SCI patients was divided into 8 homogeneous subgroups. The node specific analysis uncovered that proximal myotomes L2 and L3 were driving factors for the differentiation between walkers and non-walkers. Distal myotomes L4-S1 were revealed to be responsible for the prognostic distinction of indoor and outdoor walkers (with and without aids)., Conclusion: Stratification of a heterogeneous population with paraplegic SCI into more homogeneous subgroups, combined with the identification of underlying muscle functions prospectively determining the walking outcome, enable potential benefit for application in clinical trials and practice.

Background: Robotic lower-limb exoskeletons have the potential to provide additional clinical benefits for persons with spinal cord injury (SCI). However, high variability between protocols does not allow the comparison of study results on safety and feasibility between different exoskeletons. We therefore incorporated key aspects from previous studies into our study protocol and accordingly conducted a multicentre study investigating the safety, feasibility and usability of the ABLE Exoskeleton in clinical settings., Methods: In this prospective pretest-posttest quasi-experimental study across two SCI centres in Germany and Spain, in- and outpatients with SCI were recruited into a 12-session training and assessment protocol, utilising the ABLE Exoskeleton. A follow-up visit after 4 weeks was included to assess after-training outcomes. Safety outcomes (device-related adverse events (AEs), number of drop-outs), feasibility and usability measures (level of assistance, donning/doffing-time) were recorded at every session together with changes in gait parameters and function. Patient-reported outcome measures including the rate of perceived exertion (RPE) and the psychosocial impact of the device were performed. Satisfaction with the device was evaluated in both participants and therapists., Results: All 24 participants (45 ± 12 years), with mainly subacute SCI (< 1 year after injury) from C5 to L3, (ASIA Impairment Scale A to D) completed the follow-up. In 242 training sessions, 8 device-related AEs (pain and skin lesions) were reported. Total time for don and doff was 6:50 ± 2:50 min. Improvements in level of assistance and gait parameters (time, steps, distance and speed, p < 0.05) were observed in all participants. Walking function and RPE improved in participants able to complete walking tests with (n = 9) and without (n = 6) the device at study start (p < 0.05). A positive psychosocial impact of the exoskeleton was reported and the satisfaction with the device was good, with best ratings in safety (participants), weight (therapists), durability and dimensions (both)., Conclusions: Our study results prove the feasibility of safe gait training with the ABLE Exoskeleton in hospital settings for persons with SCI, with improved clinical outcomes after training. Our study protocol allowed for consistent comparison of the results with other exoskeleton trials and can serve as a future framework towards the standardisation of early clinical evaluations. Trial Registration https://trialsearch.who.int/ , DRKS00023503, retrospectively registered on November 18, 2020., (© 2023. The Author(s).)

Cervical spinal cord injury (SCI) causes extensive impairments for individuals which may include dextrous hand function. Although prior work has focused on the recovery at the person-level, the factors determining the recovery of individual muscles are poorly understood. Here, we investigate the muscle-specific recovery after cervical spinal cord injury in a retrospective analysis of 748 individuals from the European Multicenter Study about Spinal Cord Injury (NCT01571531). We show associations between corticospinal tract (CST) sparing and upper extremity recovery in SCI, which improves the prediction of hand muscle strength recovery. Our findings suggest that assessment strategies for muscle-specific motor recovery in acute spinal cord injury are improved by accounting for CST sparing, and complement person-level predictions., (© 2023. The Author(s).)

Background: Ischemic spinal cord injury (SCI) belongs to the heterogeneous group of non-traumatic SCI, while the course of sensorimotor and functional recovery is comparable to traumatic SCI. Recently, we derived from data of patients with traumatic SCI a valid model to predict an independent and reliable bowel management one year after SCI., Aim: To evaluate the performance of this model to predict an independent and reliable bowel management one year following ischemic SCI., Design: Prognostic study - observational study., Setting: European Multicenter Study about Spinal Cord Injury (EMSCI) ClinicalTrials.gov: NCT01571531., Population: One hundred and forty-two patients with ischemic SCI of various level and severity of injury., Methods: The prediction model relied on a single predictor collected within 40 days from injury, the International Standards for Neurological Classification of Spinal Cord Injury total motor score. Bowel outcome one year after SCI derived from the dichotomization of the Spinal Cord Independence Measure (SCIM) item 7 scores. We defined a positive outcome as independent bowel management with regular movements and appropriate timing with no or rare accidents (score of 10 in SCIM version II and score of 8 or 10 in version III)., Results: The model showed a fair discrimination with an area under the receiver operating characteristic (ROC) curve of 0.780 (95% confidence interval=0.702-0.860). In addition, the model displayed an acceptable accuracy and calibration., Conclusions: The study extends the validity of our rule to patients with ischemic SCI, thus providing the first model to predict an independent and reliable bowel management in this population., Clinical Rehabilitation Impact: The model may be employed in clinical practice to counsel patients, to define the rehabilitation aims and to estimate the need of assistance after discharge, as well as in the research field for the optimization of patients' allocation in the design of future clinical trials.

Physical activity-based rehabilitative interventions represent the main treatment concept for people suffering from spinal cord injury (SCI). The role such interventions play in the relief of neuropathic pain (NP) states is emerging, along with underlying mechanisms resulting in SCI-induced NP (SCI-NP). Animal models have been used to investigate the benefits of activity-based interventions (ABI), such as treadmill training, wheel running, walking, swimming, and bipedal standing. These activity-based paradigms have been shown to modulate inflammatory-related alterations as well as induce functional and structural changes in the spinal cord gray matter circuitry correlated with pain behaviors. Thus far, the research available provides an incomplete picture of the cellular and molecular pathways involved in this beneficial effect. Continued research is essential for understanding how such interventions benefit SCI patients suffering from NP and allow the development of individualized rehabilitative therapies. This article reviews preclinical studies on this specific topic, goes over mechanisms involved in SCI-NP in relation to ABI, and then discusses the effectiveness of different activity-based paradigms as they relate to different forms, intensity, initiation times, and duration of ABI. This article also summarizes the mechanisms of respective interventions to ameliorate NP after SCI and provides suggestions for future research directions.

Background: The epidemiological international landscape of traumatic spinal cord injury (SCI) has evolved over the last decades along with given inherent differences in acute care and rehabilitation across countries and jurisdictions. However, to what extent these differences may influence neurological and functional recovery as well as the integrity of international trials is unclear. The latter also relates to historical clinical data that are exploited to inform clinical trial design and as potential comparative data., Methods: Epidemiological and clinical data of individuals with traumatic and ischemic SCI enrolled in the European Multi-Center Study about Spinal Cord Injury (EMSCI) were analyzed. Mixed-effect models were employed to account for the longitudinal nature of the data, efficiently handle missing data, and adjust for covariates. The primary outcomes comprised demographics/injury characteristics and standard scores to quantify neurological (i.e., motor and sensory scores examined according to the International Standards for the Neurological Classification of Spinal Cord Injury) and functional recovery (walking function). We externally validated our findings leveraging data from a completed North American landmark clinical trial., Results: A total of 4601 patients with acute SCI were included. Over the course of 20 years, the ratio of male to female patients remained stable at 3:1, while the distribution of age at injury significantly shifted from unimodal (2001/02) to bimodal distribution (2019). The proportional distribution of injury severities and levels remained stable with the largest percentages of motor complete injuries. Both, the rate and pattern of neurological and functional recovery, remained unchanged throughout the surveillance period despite the increasing age at injury. The findings related to recovery profiles were confirmed by an external validation cohort (n=791). Lastly, we built an open-access and online surveillance platform ("Neurosurveillance") to interactively exploit the study results and beyond., Conclusions: Despite some epidemiological changes and considerable advances in clinical management and rehabilitation, the neurological and functional recovery following SCI has remained stable over the last two decades. Our study, including a newly created open-access and online surveillance tool, constitutes an unparalleled resource to inform clinical practice and implementation of forthcoming clinical trials targeting neural repair and plasticity in acute spinal cord injury., (© 2022. The Author(s).)

Sensorimotor function of patients with spinal cord injury (SCI) is commonly assessed according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). From the ISNCSCI segmental motor and sensory assessments, upper and lower extremity motor scores (UEMS and LEMS), sum scores of pinprick (PP) and light touch (LT) sensation, the neurological level of injury (NLI) and the classification of lesion severity according to the American Spinal Injury Association Impairment Scale (AIS) grade are derived. Changes of these parameters over time are used widely to evaluate neurological recovery. Evaluating recovery based on a single ISNCSCI scoring or classification variable, however, may misestimate overall recovery. Here, we propose an Integrated Neurological Change Score (INCS) based on the combination of normalized changes between two time points of UEMS, LEMS, and total PP and LT scores. To assess the agreement of INCS with clinical judgment of meaningfulness of neurological changes, changes of ISNCSCI variables between two time points of 88 patients from an independent cohort were rated by 20 clinical experts according to a five-categories Likert Scale. As for individual ISNCSCI variables, neurological change measured by INCS is associated with severity (AIS grade), age, and time since injury, but INCS better reflects clinical judgment about meaningfulness of neurological changes than individual ISNCSCI variables. In addition, INCS is related to changes in functional independence measured by the Spinal Cord Independence Measure (SCIM) in patients with tetraplegia. The INCS may be a useful measure of overall neurological change in clinical studies.

Background: New therapeutic approaches in neurological disorders are progressing into clinical development. Past failures in translational research have underlined the critical importance of selecting appropriate inclusion criteria and primary outcomes. Narrow inclusion criteria provide sensitivity, but increase trial duration and cost to the point of infeasibility, while broader requirements amplify confounding, increasing the risk of trial failure. This dilemma is perhaps most pronounced in spinal cord injury (SCI), but applies to all neurological disorders with low frequency and/or heterogeneous clinical manifestations., Objective: Stratification of homogeneous patient cohorts to enable the design of clinical trials with broad inclusion criteria., Methods: Prospectively-gathered data from patients with acute cervical SCI were analysed using an unbiased recursive partitioning conditional inference tree (URP-CTREE) approach. Performance in the 6-minute walk test at 6 months after injury was classified based on standardized neurological assessments within the first 15 days of injury. Functional and neurological outcomes were tracked throughout rehabilitation up to 6 months after injury., Results: URP-CTREE identified homogeneous outcome cohorts in a study group of 309 SCI patients. These cohorts were validated by an internal, yet independent, validation group of 172 patients. The study group cohorts identified demonstrated distinct recovery profiles throughout rehabilitation. The baseline characteristics of the analysed groups were compared to a reference group of 477 patients., Conclusion: URP-CTREE enables inclusive trial design by revealing the distribution of outcome cohorts, discerning distinct recovery profiles and projecting potential patient enrolment by providing estimates of the relative frequencies of cohorts to improve the design of clinical trials in SCI and beyond.

Objectives: Since their introduction, electronic International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) calculators have evolved to powerful tools providing error-free ISNCSCI classifications in education, research and clinical practice. For increased accessibility and dissemination, a multilingual support is mandatory. The aim of this work was to setup a general multilingual framework for the freely available ISNCSCI calculator ( https://ais.emsci.org ) of the European Multicenter Study about Spinal Cord Injury (EMSCI)., Methods: The graphical user interface (GUI) and PDF export of the ISNCSCI worksheet were adapted for multilingual implementations. Their language-dependent content was identified. These two steps called internationalization have to be performed by a programmer in preparation of the translations of the English terms into the target language. This step following the internationalization is called localization and needs input by a bi-lingual clinical expert. Two EMSCI partners provided Standard Mandarin Chinese and Czech translations. Finally, the translations are made available in the application., Results: The GUI and PDF export of the ISNCSCI worksheet were internationalized. The default language of the calculator is set according to the user's preferences with the additional possibility for manual language selection. The Chinese as well as a Czech translation were provided freely to the SCI community., Conclusions: The possibility of multilingual implementations independent from software developers opens the use of ISNCSCI computer algorithms as an efficient training tool on a larger scale., (© 2021. The Author(s).)

Study Design: Prospective pre-post study., Objectives: International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) represents the most frequently used assessment to determine the level and severity of a spinal cord injury (SCI). The guidelines for ISNCSCI are complex and challenging. Knowledge of its correct execution needs to be imparted precisely. The aim of this study was to investigate whether hands-on instructional courses can increase the knowledge of the ISNCSCI examination guidelines., Setting: European Multicenter Study about SCI., Methods: Before and after the instructional courses, participants were asked to complete questionnaires. The set of questions covered the most important aspects of the examination guidelines. Attendees were asked to self-rate their occupation and experience in ISNCSCI., Results: The comparison of pretest and posttest results of 164 attendees from 2014 to 2018 revealed an improvement of knowledge reflected by an increase of correct answers from 66 ± 17% before to 89 ± 11% after the course (p < 0.01). The improvement was not associated with occupation (p > 0.1). However, the correctness of pretest results differed concerning both the period of experience with ISNCSCI (p < 0.05) and the course language (p < 0.01), while the frequency of execution resulted in differences in the posttest (p = 0.01)., Conclusions: Instructional courses substantially improve knowledge of the ISNCSCI examination guidelines. Differences in knowledge present before the course leveled off after the course. Comprehensive theoretical training is strongly recommended to ensure reliability and validity of ISNCSCI examinations in clinical routine and research. Albeit being practiced in the instructional courses, the benefit of hands-on training still needs to be systematically evaluated in future studies., (© 2020. The Author(s).)

Objective: In Germany, treatment paths for patients with acute spinal cord injury (SCI) differ considerably depending on intrinsic, disease-specific and extrinsic factors. Which of these factors are associated with improved outcome with fewer subsequent complications and inpatient re-admissions is not clear. The German-wide, patient-centered, web-based ParaReg registry will be implemented to improve the long-term quality of patient care and the planning of treatment paths with increased cost-effectiveness., Methods: In the 2017-18 conceptualization phase, the data model of the registry was developed in an iterative process of the ParaReg steering committee together with the extended DMGP board and patient representatives. In ParaReg, routine social and medical data as well as internationally established neurological, functional and participation scores will be documented. The assignment of a unique patient ID allows a lifelong, cross-center documentation of inpatient stays in one of the 27 SCI centers organized in the German-speaking Medical Society for SCI (DMGP). The ParaReg data protection concept and patient information/consent are based on the Open Source Registry for Rare Diseases (OSSE) which were extended by GDPR-relevant aspects., Results: In the realization phase, which started in 2019, the information technology infrastructure was implemented according to the clinical ID management module of the Technology and Methods Platform for Networked Medical Research (TMF). In parallel, the legal and ethical prerequisites for registry operation under the patronage of the DMGP were created. Recommendations of the working group data protection of the TMF were integrated into ParaReg's data protection concept. Based on the feedback from the alpha test phase with documentation of the hospitalization data of 40 patients, the ergonomics of the electronic case report forms were improved in particular for data entry on mobile devices., Conclusion: After completion of the monocentric alpha test phase, the multicenter data acquisition was started in 5 DMGP-SCI centers. The sustainability of ParaReg is ensured by the structural and financial support of the DMGP after expiry of the funding by the German Federal Ministry of Education and Research (BMBF)., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht. Die Autorinnen/Autoren erhalten eine finanzielle Förderung vom BMBF, der DMGP und des Universitätsklinikums Heidelberg., (Thieme. All rights reserved.)

Study Design: Multicenter observational study., Objective: To describe the long-term outcome of functional independence and quality of life (QoL) for individuals with traumatic and ischemic SCI beyond the first year after injury., Setting: A multicenter study in Germany., Methods: Participants of the European multicenter study about spinal cord injury (EMSCI) of three German SCI centers were included and followed over time by the German spinal cord injury cohort study (GerSCI). Individuals' most recent spinal cord independence measure (SCIM) scores assessed by a clinician were followed up by a self-report (SCIM-SR) and correlated to selected items of the WHO short survey of quality of life (WHO-QoL-BREF)., Results: Data for 359 individuals were obtained. The average time passed the last clinical SCIM examination was 81.47 (SD 51.70) months. In total, 187 of the 359 received questionnaires contained a completely evaluable SCIM-SR. SCIM scores remained stable with the exception of reported management of bladder and bowel resulting in a slight decrease of SCIM-SR of -2.45 points (SD 16.81). SCIM-SR scores showed a significant correlation with the selected items of the WHO-QoL-BREF (p < 0.01) with moderate to strong influence., Conclusion: SCIM score stability over time suggests a successful transfer of acquired independence skills obtained during primary rehabilitation into the community setting paralleled by positively related QoL measurements but bladder and bowel management may need special attention., (© 2021. The Author(s).)

Background: A central goal of rehabilitation in patients with paralysis syndromes after stroke or spinal cord injury (SCI) is to restore independent mobility as a pedestrian or wheelchair user. However, after acute rehabilitation, the mobility frequently deteriorates in the ambulatory setting, despite the delivery of rehabilitative interventions such as physical therapy or the prescription of assistive devices. The aim of the NeuroMoves study is to identify factors that are associated with changes of mobility in the ambulatory setting after acute inpatient rehabilitation, with a particular focus on participation according to the ICF (International Classification of Functioning, Disability and Health)., Methods: The NeuroMoves study is intended as a national multicenter observational cohort study with 9 clinical sites in Germany. A total of 500 patients with mobility-restricting paralysis syndromes (i.e. stroke or SCI) are to be recruited during acute inpatient rehabilitation prior to discharge to the ambulatory setting. Patients will have 8 months of follow-up in the ambulatory setting. Three study visits at the clinical sites (baseline, midterm, and final) are planned at 4-months intervals. The baseline visit is scheduled at the end of the acute inpatient rehabilitation. During the visits, demographical data, neurological, functional, quality of life, and implementation measures will be assessed. At baseline, each study participant receives an activity tracker (sensor for recording ambulatory mobility) along with a tablet computer for home use over the 8 months study duration. While mounted, the activity tracker records mobility data from which the daily distance covered by walking or wheelchair use can be calculated. Customized applications on the tablet computer remind the study participants to answer structured questionnaires about their health condition and treatment goals for physical therapy. Using the study participants' tablet, therapists will be asked to answer structured questionnaires concerning treatment goals and therapeutic measures they have applied. The primary analysis concerns the association between mobility (daily distance covered) and the degree of participation-oriented rehab interventions. Further exploratory analyses are planned., Discussion: The findings could inform healthcare decision-making regarding ambulatory care in Germany focusing on mobility-promoting interventions for patients with mobility-restricting paralysis syndromes., Study Registration: German Clinical Trials Register, DRKS-ID: DRKS00020487 (18.02.2020).

Study Design: Chart reviews were combined with neurological and functional outcome data obtained from the prospective European Multicenter Study on Spinal Cord Injury (EMSCI, www.emsci.org)., Objectives: To determine if strict physical isolation of multidrug-resistant organisms (MDRO)-positive patients negatively affects neurological recovery and functional outcome in the first year after acute spinal cord injury (SCI)., Setting: SCI Center Heidelberg University Hospital., Methods: Individuals with acute (< 6 weeks) traumatic or ischemic SCI were included. During primary comprehensive care, isolated MDRO-positive patients (n = 13) were compared with a MDRO-negative control group (n = 13) matched for functional (Spinal Cord Independence Measure-SCIM) and neurological impairment (motor scores based on the International Standards for Neurological Classification of Spinal Cord Injury-ISNCSCI) at an early stage up to 40 days after SCI. SCIM scores and motor scores were obtained at 12 weeks (intermediate stage) and 24 or 48 weeks (late stage) after SCI., Results: Isolated MDRO-positive (median duration of hospitalization: 175 days, 39% of inpatient stay under isolation measures) and non-isolated MDRO-negative (median duration of hospitalization: 161 days) patients showed functional and neurological improvements, which were not statistically different between groups at the intermediate and late stage., Conclusion: Prolonged isolation due to MDRO colonization for over a third of the inpatient comprehensive care period does not appear to impair neurological recovery and functional outcome within the first year after SCI., Competing Interests: The authors have declared that no competing interests exist.

In many preclinical spinal cord injury (SCI) studies, assessment of locomotion recovery is key to understanding the effectiveness of the experimental intervention. In such rat SCI studies, the most basic locomotor recovery scoring system is a subjective observation of animals freely roaming in an open field, the Basso Beattie Bresnahan (BBB) score. In comparison, CatWalk is an automated gait analysis system, providing further parameter specifications. Although together the CatWalk parameters encompass gait, studies consistently report single parameters, which differ in significance from other behavioral assessments. Therefore, we believe no single parameter produced by the CatWalk can represent the fully-coordinated motion of gait. Typically, other locomotor assessments, such as the BBB score, combine several locomotor characteristics into a representative score. For this reason, we ranked the most distinctive CatWalk parameters between uninjured and SC injured rats. Subsequently, we combined nine of the topmost parameters into an SCI gait index score based on linear discriminant analysis (LDA). The resulting combination was applied to assess gait recovery in SCI experiments comprising of three thoracic contusions, a thoracic dorsal hemisection, and a cervical dorsal column lesion model. For thoracic lesions, our unbiased machine learning model revealed gait differences in lesion type and severity. In some instances, our LDA was found to be more sensitive in differentiating recovery than the BBB score alone. We believe the newly developed gait parameter combination presented here should be used in CatWalk gait recovery work with preclinical thoracic rat SCI models., (Copyright © 2021 Timotius et al.)

There is much controversy about the potential impact of spinal cord injury (SCI) on brain anatomy and function, which is mirrored in the substantial divergence of findings between animal models and human imaging studies. Given recent advances in quantitative magnetic resonance imaging (MRI) we sought to tackle the unresolved question about the link between the presumed injury associated volume differences and underlying brain tissue property changes in a cohort of chronic complete SCI patients. Using the established computational anatomy methods of voxel-based morphometry (VBM) and voxel-based quantification (VBQ), we performed statistical analyses on grey and white matter volumes as well as on parameter maps indicative for myelin, iron, and free tissue water content in the brain of complete SCI patients (n = 14) and healthy individuals (n = 14). Our regionally unbiased white matter analysis showed a significant volume reduction of the dorsal aspect at the junction between the most rostral part of the spinal cord and the medulla oblongata consistent with Wallerian degeneration of proprioceptive axons in the dorsal column tracts in SCI subjects. This observation strongly correlated with spinal cord atrophy assessed by quantification of the spinal cord cross-sectional area at the cervical level C2/3. These findings suggest that Wallerian degeneration of the dorsal column tracts represents a main contributor to the observed spinal cord atrophy, which is highly consistent with preclinical histological evidence of remote changes in the central nervous system secondary to SCI. Structural changes in other brain regions representing remote changes in the course of chronic SCI could neither be confirmed by conventional VBM nor by VBQ analysis. Whether and how MRI based brain morphometry and brain tissue property analysis will inform clinical decision making and clinical trial outcomes in spinal cord medicine remains to be determined., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Study Design: Retrospective analysis of prospectively collected data., Objective: Central cord syndrome (CCS) is reported to have better outcomes than other cervical lesions, especially for ambulation and bladder recovery. However, a formal comparison between patients with CCS and other incomplete cervical spinal cord injuries (iCSCI) is lacking. Aim of the study is to investigate the neurological and functional outcomes in patients with or without CCS., Setting: European Multicenter Study., Methods: Data following SCI were derived from the European Multicenter Study about Spinal Cord Injury Database. CCS was diagnosed based on a difference of at least ten points of motor score in favour of the lower extremities. Patients were evaluated at 30 days, 6 months and 1 year from injury. The neurological and functional data were collected at each time point based on the International Standards for Neurological Classification of Spinal Cord injury (ISNSCI) and Spinal Cord Independence Measure (SCIM). Patients were selected with a matching procedure based on lesion severity, neurological level of injury (NLI) and age. Evaluation of the outcomes was performed by means of two-way Anova for repeated measures., Results: The matching produced 110 comparable dyads. At all time points, upper extremity motor scores remained lower than lower extremity motor scores in CCS compared with iCSCI. With regard to daily life independence, both cohorts achieved comparable improvements in self-care sub-scores between T0 and T2 (6.6 ± 6.5 in CCS vs 8.2 ± 6.9 in iCSCI, p = 0.15) but this sub-score was significantly lower in CCS compared with iCSCI (3.6 ± 5.2 in CCS vs 7.3 ± 7.0 in iCSCI at T0, 13.7 ± 6.2 vs 16.5 ± 5.7 at T2), while the other sub-scores were comparable., Conclusions: In contrast to previous reports, people with CCS have poorer outcomes of self-care ability compared with iCSCI.

Study Design: Multicenter prospective cohort., Objective: To discern neurological- and functional recovery in patients with a traumatic thoracic spinal cord injury (TSCI), conus medullaris syndrome (CMS), and cauda equina syndrome (CES)., Setting: Specialized spinal cord injury centers in Europe., Method: Lower extremity motor score (LEMS) and spinal cord independent measure (SCIM) scores from patients with traumatic TSCI, CMS, and CES were extracted from the EMSCI database. Scores from admittance and during rehabilitation at 1, 3, 6, and 12 months were compared. Linear mixed models were used to statistically analyse differences in outcome, which were corrected for the ASIA Impairment Scale (AIS) in the acute phase., Results: Data from 1573 individuals were analysed. Except for the LEMS in patients with a CES AIS A, LEMS, and SCIM significantly improved over time for patients with a TSCI, CMS, and CES. Irrespectively of the AIS score, recovery in 12 months after trauma as measured by the LEMS showed a statistically significant difference between patients with a TSCI, CMS, and CES. Analysis of SCIM score showed no difference between patients with TSCI, CMS, or CES., Conclusion: Difference in recovery between patients with a traumatic paraplegia is based on neurological (motor) recovery. Regardless the ceiling effect in CES patients, patients with a mixed upper and lower motor neuron syndrome (CMS) showed a better recovery compared with patients with a upper motor neuron syndrome (TSCI). These findings enable stratifications of patients with paraplegia according to the level and severity of SCI.

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

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

Background . The relative rarity of ischemic compared with traumatic spinal cord injury (SCI) has limited a comparison of the outcomes of these conditions. Objective . To investigate the neurological and functional recovery of ischemic compared with traumatic acute SCI. Methods . Data were derived from the European Multicenter Study Spinal Cord Injury database. Patients with ischemic (iSCI) or traumatic SCI (tSCI), aged 18 years or older were evaluated at different time points from incidence: at about 1 month, 3 months, and 6 months. The neurological status was assessed at each time point by the International Standards for Neurological Classification of Spinal Cord Injury and the functional status by the Spinal Cord Independence Measure. Walking ability was evaluated by Walking Index for Spinal Cord Injury, 10-Meter Walk Test, and 6-Minute Walk Test. Because of the imbalances of the 2 groups in respect to size and lesion severity, a matching procedure according to age, neurological level, and severity of injury was performed. Outcomes evaluation was performed by means of a 2-way repeated-measures ANOVA. Results . The matching procedure resulted in 191 pairs. Both groups significantly improved from about 15 days after the lesion to 6 months. No differences were found in the course of neurological and functional recovery of iSCI compared with tSCI. Conclusions . This analysis from a representative cohort of participants revealed that from 15 days following the cord damage onward, the outcomes after iSCI and tSCI are comparable. This finding supports the potential enrolment of patients with acute iSCI into clinical trials from that point in time after the event and an evaluation up to 6 months afterward.

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

Study Design: A prospective single arm study., Objectives: Previously we have demonstrated that magnetic resonance (MR) defecography is feasible in participants with complete spinal cord injury (SCI). The main aim of this study is to evaluate whether MR defecography can provide objective parameters correlating with the clinical manifestations of neurogenic bowel dysfunction (NBD) in participants with SCI., Setting: A monocentric study in a comprehensive care university hospital Spinal Cord Injury Center., Methods: Previously published MR defecography parameters (anorectal angle (ARA), hiatal descent (M-line) and hiatal width (H-line)) of twenty participants with SCI were now compared to a standardized clinical assessment of NBD. Descriptive statistics, correlations and t-tests for independent samples were calculated., Results: The significantly higher values for the ARA at rest and M-line at rest in participants with SCI correlated with the clinical assessment of bowel incontinence. Furthermore, in nearly half of the investigated SCI cohort the normally positive difference between ARA, M-line and H-line at rest and during defecation became negative suggesting pelvic floor dyssynergia as a potential mechanism underlying constipation in people with complete SCI. In fact, these participants showed a more severe clinical presentation of NBD according to the total NBD score., Conclusions: MR defecography provides objective parameters correlating with clinical signs of NBD, such as constipation and bowel incontinence. Therefore, MR defecography can support pathophysiology-based decision-making with respect to specific therapeutic interventions, which should help to improve the management of NBD.

Background. Predicting functional outcomes after traumatic spinal cord injury (SCI) is essential for counseling, rehabilitation planning, and discharge. Moreover, the outcome prognosis is crucial for patient stratification when designing clinical trials. However, no valid prediction rule is currently available for bowel outcomes after a SCI. Objective . To generate a model for predicting the achievement of independent, reliable bowel management at 1 year after traumatic SCI. Methods . We performed multivariable logistic regression analyses of data for 1250 patients with traumatic SCIs that were included in the European Multicenter Study about Spinal Cord Injury. The resulting model was prospectively validated on data for 186 patients. As potential predictors, we evaluated age, sex, and variables from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) and the Spinal Cord Independence Measure (SCIM), measured within 40 days of the injury. A positive outcome at 1 year post-SCI was assessed with item 7 of the SCIM. Results . The model relied on a single predictor, the ISNCSCI total motor score-that is, the sum of muscle strengths in 5 key muscle groups in each limb. The area under the receiver operating characteristics curve (aROC) was 0.837 (95% CI: 0.815-0.859). The prospective validation confirmed high predictive power: aROC = 0.817 (95% CI: 0.754-0.881). Conclusions . We generated a valid model for predicting independent, reliable bowel management at 1 year after traumatic SCI. Its application could improve counseling, optimize patient-tailored rehabilitation planning, and become crucial for appropriate patient stratification in future clinical trials.

Study Design: Narrative review by individuals experienced in the recruitment of participants to neurotherapeutic clinical trials in spinal cord injury (SCI)., Objectives: To identify key problems of recruitment and explore potential approaches to overcoming them., Methods: Published quantitative experience with recruitment of large-scale, experimental neurotherapeutic clinical studies targeting central nervous system and using primary outcome assessments validated for SCI over the last 3 decades was summarized. Based on this experience, potential approaches to improving recruitment were elicited from the authors., Results: The rate of recruitment has varied between studies, depending on protocol design and other factors, but particularly inclusion/exclusion criteria. The recruitment rate also ranged over an order of magnitude between individual centers in a given study. In older multicenter studies, average recruitment rate was approximately one person per study center per month. More recent trials experienced lower rates of recruitment and potential reasons for this trend were examined. The current roles and potential of various stakeholder organizations in addressing problems of recruitment were explored. In addition, recent developments in methodology may help reduce the number of subjects required for well-powered studies., Conclusions: Several approaches are emerging to improve clinical trial design, efficacy outcome measures, and quantifiable surrogate markers, all of which should reduce the number of participants required for adequate statistical power. There is a growing sense of cooperation between various stakeholders but more should be done to bring together consumer and provider groups to improve recruitment and the effectiveness and relevance of neurotherapeutic clinical trials.

The translation of therapeutic interventions to humans with spinal cord injury with the goal of promoting growth and repair in the central nervous system could, inadvertently, drive mechanisms associated with the development of neuropathic pain. A framework is needed to evaluate the probability that a therapeutic intervention for acute spinal cord injury modifies the progression of neuropathic pain. We analyzed a large, longitudinal dataset from the European Multi-Center Study about Spinal Cord Injury (EMSCI) and compared these observations with a previously published Swedish/Danish cohort. A meta-analysis was performed to produce aggregate estimates for the transition period between 1-6 months and the transition period between 1-12 months after injury. A secondary analysis used logistic regression to explore associations between the progression of neuropathic pain and demographics, pain characteristics, and injury characteristics. For overall neuropathic pain, 72% presenting with pain symptoms at one month reported persisting symptoms at six months, and 23% who did not have neuropathic pain at one month later had it develop. From 1-12 months, there was a similar likelihood of pain persisting (69%) and slightly higher rate of pain developing (36%). Characteristics that were significantly associated with the progression of pain included age and sensory and motor preservation. We provide historical benchmarks for estimating the progression of neuropathic pain during the first year after acute SCI. This information will be useful for comparison and evaluating safety during early phase acute spinal cord injury trials.

Impact Statement: Axonal bridging across a lesion in the injured spinal cord requires a growth substrate and guidance cues. Using alginate hydrogels with capillary channels we show that poly-l-ornithine and laminin can be stably bound and improve cell adhesion and neurite growth in vitro , and axon growth in vivo by enhancing host cell infiltration in the injured spinal cord. Filling of coated hydrogels with postnatal astrocytes further increases short-distance axon growth and results in a continuous astroglial substrate across the host/graft interface. Thus, positively charged bioactive molecules can be stably bound to anisotropic capillary alginate hydrogels and early astrocytes further promote tissue integration.

Objective: Determining differences in neurological and functional outcome between adolescents and adults after acute traumatic spinal cord injury (SCI)., Design: Retrospective, multi-center case-control study., Methods: 100 cases of patients under 18 years at accident with acute traumatic cervical SCI admitted to SCI centers participating in the European Multi-center study about SCI (EMSCI) between January 2005 and April 2016 were reviewed. According to their age at accident, age 13 to 17, patients were selected for the adolescent group. After applying in- and exclusion criteria 32 adolescents were included. Each adolescent patient was matched with two adult SCI patients for analysis., Outcome Measures: ASIA Impairment scale (AIS) grade, neurological, sensory, motor level, total motor score, and Spinal Cord Independence Measure (SCIM III) total score., Results: Mean AIS conversion, neurological, motor and sensory levels as well as total motor score showed no significantly statistical difference in adolescents compared to the adult control group after follow up of 6 months. Significantly higher final SCIM scores (p < 0.05) in the adolescent group compared to adults as well as a strong trend for a higher gain in SCIM score (p < 0.061) between first and last follow up was found., Conclusions: Neurological outcome after traumatic cervical SCI is not superior in adolescents compared to adults in this cohort. Significantly higher SCIM scores indicate more functional gain for the adolescent patients after traumatic cervical SCI. Juvenile age appears to be an independent predictor for a better functional outcome., (Copyright © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

A large proportion of patients suffering from spinal cord injury (SCI) develop chronic central neuropathic pain. Previously, we and others have shown that sensorimotor training early after SCI can prevent the development of mechanical allodynia. To determine whether training initiated in the subchronic/chronic phase remains effective, correlates of below-level neuropathic pain were analyzed in the hindpaws 5-10 weeks after a moderate T11 contusion SCI (50 kDyn) in adult female C57BL/6 mice. In a comparison of SCI and sham mice 5 weeks post-injury, about 80% of injured animals developed mechanical hypersensitivity to light mechanical stimuli, whereas testing of noxious stimuli revealed hypo-responsiveness. Thermal sensitivity testing showed a decreased response latency after injury. Without intervention, mechanical and thermal hyper-responsiveness were evident until the end of the experiment (10 weeks). In contrast, treadmill training (2 × 15 min/day; 5 × /week) initiated 6 weeks post-injury resulted in partial amelioration of pain behavior and this effect remained stable. Analysis of calcitonin gene-related peptide (CGRP)-labeled fibers in lamina III-IV of the lumbar dorsal horn revealed an increase in labeling density after SCI. This was not due to changes in the number or size distribution of CGRP-labeled lumbar dorsal root ganglion neurons. Treadmill training reduced the CGRP-labeling density in the spinal cord of injured mice, whereas the density of non-peptidergic isolectin-B4 (IB4) + fibers showed no changes in lamina IIi and a slight reduction of sparse IB4 labeling in laminae III-IV. Thus, sensorimotor activity initiated in the subchronic/chronic phase of SCI remains effective in ameliorating pain behavior and influencing structural changes of the nociceptive system.

Following a spinal cord injury (SCI) a growth aversive environment forms, consisting of a fibroglial scar and inhibitory factors, further restricting the already low intrinsic growth potential of injured adult central nervous system (CNS) neurons. Previous studies have shown that local administration of the microtubule-stabilizing drug paclitaxel or epothilone B (Epo B) reduce fibrotic scar formation and axonal dieback as well as induce axonal growth/sprouting after SCI. Likewise, systemic administration of Epo B promoted functional recovery. In this study, we investigated the effects of epothilone D (Epo D), an analog of Epo B with a possible greater therapeutic index, on fibrotic scarring, axonal sprouting and functional recovery after SCI. Delayed systemic administration of Epo D after a moderate contusion injury (150 kDyn) in female Fischer 344 rats resulted in a reduced number of footfalls when crossing a horizontal ladder at 4 and 8 weeks post-injury. Hindlimb motor function assessed with the BBB open field locomotor rating scale and Catwalk gait analysis were not significantly altered. Moreover, formation of laminin positive fibrotic scar tissue and 5-HT positive serotonergic fiber length caudal to the lesion site were not altered after treatment with Epo D. These findings recapitulate a functional benefit after systemic administration of a microtubule-stabilizing drug in rat contusion SCI., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Neutralization of central nervous system neurite growth inhibitory factors, for example, Nogo-A, is a promising approach to improving recovery following spinal cord injury (SCI). In animal SCI models, intrathecal delivery of anti-Nogo-A antibodies promoted regenerative neurite growth and functional recovery., Objective: This first-in-man study assessed the feasibility, safety, tolerability, pharmacokinetics, and preliminary efficacy of the human anti-Nogo-A antibody ATI355 following intrathecal administration in patients with acute, complete traumatic paraplegia and tetraplegia., Methods: Patients (N = 52) started treatment 4 to 60 days postinjury. Four consecutive dose-escalation cohorts received 5 to 30 mg/2.5 mL/day continuous intrathecal ATI355 infusion over 24 hours to 28 days. Following pharmacokinetic evaluation, 2 further cohorts received a bolus regimen (6 intrathecal injections of 22.5 and 45 mg/3 mL, respectively, over 4 weeks)., Results: ATI355 was well tolerated up to 1-year follow-up. All patients experienced ≥1 adverse events (AEs). The 581 reported AEs were mostly mild and to be expected following acute SCI. Fifteen patients reported 16 serious AEs, none related to ATI355; one bacterial meningitis case was considered related to intrathecal administration. ATI355 serum levels showed dose-dependency, and intersubject cerebrospinal fluid levels were highly variable after infusion and bolus injection. In 1 paraplegic patient, motor scores improved by 8 points. In tetraplegic patients, mean total motor scores increased, with 3/19 gaining >10 points, and 1/19 27 points at Week 48. Conversion from complete to incomplete SCI occurred in 7/19 patients with tetraplegia., Conclusions: ATI335 was well tolerated in humans; efficacy trials using intrathecal antibody administration may be considered in acute SCI.

Activity dependent plasticity is a key mechanism for the central nervous system (CNS) to adapt to its environment. Whether neuronal activity also influences axonal regeneration in the injured CNS, and whether electrical stimulation (ES) can activate regenerative programs in the injured CNS remains incompletely understood. Using KCl-induced depolarization, in vivo ES followed by ex-vivo neurite growth assays and ES after spinal cord lesions and cell grafting, we aimed to identify parameters important for ES-enhanced neurite growth and axonal regeneration. Using cultures of sensory neurons, neurite growth was analyzed after KCl-induced depolarization for 1-72h. Increased neurite growth was detected after short-term stimulation and after longer stimulation if a sufficient delay between stimulation and growth measurements was provided. After in vivo ES (20Hz, 2× motor threshold, 0.2ms, 1h) of the intact sciatic nerve in adult Fischer344 rats, sensory neurons showed a 2-fold increase in in vitro neurite length one week later compared to sham animals, an effect not observed one day after ES. Longer ES (7h) and repeated ES (7days, 1h each) also increased growth by 56-67% one week later, but provided no additional benefit. In vivo growth of dorsal column sensory axons into a graft of bone marrow stromal cells 4weeks after a cervical spinal cord lesion was also enhanced with a single post-injury 1h ES of the intact sciatic nerve and was also observed after repeated ES without inducing pain-like behavior. While ES did not result in sensory functional recovery, our data indicate that ES has time-dependent influences on the regenerative capacity of sensory neurons and might further enhance axonal regeneration in combinatorial approaches after SCI., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Study Design: Prospective observational multicenter study., Objectives: Investigation of content, duration and adjustment of physical therapy for the rehabilitation of ambulation in acute spinal cord injury (SCI)., Setting: European Multicenter Study of SCI (EMSCI)., Methods: Physical therapy interventions during acute in-patient rehabilitation of eighty incomplete SCI patients (AIS B, C, D all lesion levels) were recorded using the SCI - Intervention Classification System. Mobility was documented using the Spinal Cord Independence Measurement (SCIM III), demographics and clinical data were retrieved from the EMSCI database., Results: Overall recovery of locomotor function was categorized into three outcome groups (G1-G3). Of 76 initial wheelchair-using patients, 53.9% remained wheelchair user (G1), 25% regained moderate (G2) and 21.1% good walking (G3) capability. Strength training was the most frequently applied intervention of body function/-structure across all outcome groups (about 30% of all interventions), while interventions focusing on muscle tone and respiration were predominantly applied in wheelchair-dependent patients. Activity-focused interventions of transfer, transition, sitting were trained most intensively in outcome group G1, while walking and swimming were increasingly trained in patients with moderate and good walking outcomes. Physical therapy interventions of assistive and active trainings as well as corresponding training environments changed with the recovery of locomotor function., Conclusions: Physical therapy of locomotor function is targeted to individual patients' conditions and becomes adjusted to the progress of ambulation. Although the involved clinical sites were not following explicitly standardized rehabilitation programs, common patterns can be discerned which may form the basis of prospective standardized programs.

Background: Neuropathic pain (NeuP) is a frequent sequel of spinal cord injury (SCI). The SCI Pain Instrument (SCIPI) was developed as a SCI-specific NeuP screening tool. A preliminary validation reported encouraging results requiring further evaluation in terms of psychometric properties. The painDETECT questionnaire (PDQ), a commonly applied NeuP assessment tool, was primarily validated in German, but not specifically developed for SCI and not yet validated according to current diagnostic guidelines. We aimed to provide convergent construct validity and to identify the optimal item combination for the SCIPI. The PDQ was re-evaluated according to current guidelines with respect to SCI-related NeuP., Methods: Prospective monocentric study. Subjects received a neurological examination according to the International Standards for Neurological Classification of SCI. After linguistic validation of the SCIPI, the IASP-grading system served as reference to diagnose NeuP, accompanied by the PDQ after its re-evaluation as binary classifier. Statistics were evaluated through ROC-analysis, with the area under the ROC curve (AUROC) as optimality criterion. The SCIPI was refined by systematic item permutation., Results: Eighty-eight individuals were assessed with the German SCIPI. Of 127 possible combinations, a 4-item-SCIPI (cut-off-score = 1.5/sensitivity = 0.864/specificity = 0.839) was identified as most reasonable. The SCIPI showed a strong correlation (r sp  = 0.76) with PDQ. ROC-analysis of SCIPI/PDQ (AUROC = 0.877) revealed comparable results to SCIPI/IASP (AUROC = 0.916). ROC-analysis of PDQ/IASP delivered a score threshold of 10.5 (sensitivity = 0.727/specificity = 0.903)., Conclusion: The SCIPI is a valid easy-to-apply NeuP screening tool in SCI. The PDQ is recommended as complementary NeuP assessment tool in SCI, e.g. to monitor pain severity and/or its time-dependent course., Significance: In SCI-related pain, both SCIPI and PainDETECT show strong convergent construct validity versus the current IASP-grading system. SCIPI is now optimized from a 7-item to an easy-to-apply 4-item screening tool in German and English. We provided evidence that the scope for PainDETECT can be expanded to individuals with SCI., (© 2017 European Pain Federation - EFIC®.)

Grafting of cell-seeded alginate capillary hydrogels into a spinal cord lesion site provides an axonal bridge while physically directing regenerating axonal growth in a linear pattern. However, without an additional growth stimulus, bridging axons fail to extend into the distal host spinal cord. Here we examined whether a combinatory strategy would support regeneration of descending axons across a cervical (C5) lateral hemisection lesion in the rat spinal cord. Following spinal cord transections, Schwann cell (SC)-seeded alginate hydrogels were grafted to the lesion site and AAV5 expressing brain-derived neurotrophic factor (BDNF) under control of a tetracycline-regulated promoter was injected caudally. In addition, we examined whether SC injection into the caudal spinal parenchyma would further enhance regeneration of descending axons to re-enter the host spinal cord. Our data show that both serotonergic and descending axons traced by biotinylated dextran amine (BDA) extend throughout the scaffolds. The number of regenerating axons is significantly increased when caudal BDNF expression is activated and transient BDNF delivery is able to sustain axons after gene expression is switched off. Descending axons are confined to the caudal graft/host interface even with continuous BDNF expression for 8weeks. Only with a caudal injection of SCs, a pathway facilitating axonal regeneration through the host/graft interface is generated allowing axons to successfully re-enter the caudal spinal cord., Statement of Significance: Recovery from spinal cord injury is poor due to the limited regeneration observed in the adult mammalian central nervous system. Biomaterials, cell transplantation and growth factors that can guide axons across a lesion site, provide a cellular substrate, stimulate axon growth and have shown some promise in increasing the growth distance of regenerating axons. In the present study, we combined an alginate biomaterial with linear channels with transplantation of Schwann cells within and beyond the lesion site and injection of a regulatable vector for the transient expression of brain-derived neurotrophic factor (BDNF). Our data show that only with the full combination axons extend across the lesion site and that expression of BDNF beyond 4weeks does not further increase the number of regenerating axons., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Study Design: Retrospective statistical analysis of database., Objective: Spinal cord injury (SCI) clinical trials are challenged to enroll participants, and early trial outcomes have often been equivocal. We hypothesized that a specifically designed novel true linear interval-scaled outcome measure targeted to simultaneously track a broad range of SCI will enable more inclusive enrollment of participants and valid comparisons of functional changes after SCI., Methods: To define a single SCI measurement framework, we used items from existing measures. To evaluate linearity and validity of the measure, we used rigorous psychometric Rasch analysis on two data sets from over 2500 traumatic SCI participants (all levels and severities of SCI) within the EMSCI (European Multicenter study about SCI) database., Results: Volitional performance was found to be the unidimensional construct that would detect and track a treatment effect from a central nervous system-directed therapeutic. Along with early evidence for voluntary neurological control of upper-extremity muscle contractions, volitional performance is best described by goal-directed activities of daily living that are increasingly difficult to re-acquire when activity within more caudal spinal segments is required. Validity of the Spinal Cord Ability Ruler (SCAR) as a linear interval construct was confirmed with Rasch analysis. All measurement items were properly ordered, as well as being precise and stable across clinically relevant groups. Only 5/24 items had some misfit. Targeting was excellent over time after SCI, with few gaps and only modest floor and ceiling effects (3% each)., Conclusions: SCAR is a quantitative linear measure of volitional performance across an inclusive range of tetraplegic and paraplegic SCI.

Objectives: Pressure ulcers impose a major lifetime medical problem to patients with high-grade spinal cord injury (SCI). For patients with stages 3-4 pressure ulcers, plastic surgery is often the only remaining treatment option. Despite considerable flap failure rates of around 30%, only sparse knowledge exists on predictors for flap failure. Hence, identification of predictors for flap failures is needed., Methods: We prospectively enrolled 38 SCI patients with stages 3-4 pressure ulcers scheduled for plastic surgery. Preoperative wound swabs, intraoperative tissue samples and postoperative drainage liquids were microbiologically analyzed. In multivariable logistic regression analyses, bacterial loads of deep tissue cultures of intraoperative samples as well as other clinical variables were analyzed with respect to the prediction of flap failures., Results: The flap failure rate was 27.5%. Bacterial loads of deep tissue cultures were not predictive for flap failure, neither was the colonization with a specific bacterial strain. We observed a considerable fluctuation of microbiological environment from initial swab cultures, intraoperative samples and postoperative drainage fluids. Antibioprophylaxis was sufficient in only 75% of deep tissue cultures and 69% of drainage fluids. Insufficient antibioprophylaxis was associated with a higher flap failure rates (odds ratio 6.3, confidence interval 1.2-41.0)., Conclusion: After inpatient wound conditioning, bacterial load analysis of intraoperative wound tissue cultures is ineffective in order to predict flap failure rates in SCI patients with stages 3-4 pressure ulcers after flap surgery. Instead, insufficient antibioprophylaxis might be a factor contributing to flap failure.

Introduction: To investigate whether MR-defecography can be employed in sensorimotor complete spinal cord injury (SCI) subjects as a potential diagnostic tool to detect defecational disorders associated with neurogenic bowel dysfunction (NBD) using standard parameters for obstructed defecation., Material and Methods: In a prospective single centre clinical trial, we developed MR-defecography in traumatic sensorimotor complete paraplegic SCI patients with upper motoneuron type injury (neurological level of injury T1 to T10) using a conventional 3T scanner. Defecation was successfully induced by eliciting the defecational reflex after rectal filling with ultrasonic gel, application of two lecicarbon suppositories and digital rectal stimulation. Examination was performed with patients in left lateral decubitus position using T2-weighted turbo spin echo sequence in the sagittal plane at rest (TE 89ms, TR 3220ms, FOV 300mm, matrix 512×512, ST 4mm) and ultrafast-T2-weighted-sequence in the sagittal plane with repeating measurements (TE 1.54ms, TR 3.51ms, FOV 400mm, matrix 256×256, ST 6mm). Changes of anorectal angle (ARA), anorectal descent (ARJ) and pelvic floor weakness were documented and measured data was compared to reference values of asymptomatic non-SCI subjects in the literature to assess feasibility., Results: MR-defecography provides evaluable imaging sequences of the induced evacuation phase in SCI patients. Measurement results for ARA, ARJ, hiatal width (H-line) and hiatal descent (M-line) deviate significantly from reference values in the literature in asymptomatic subjects without SCI. The overall mean values in our study for SCI patients were: ARA (rest) 127.3°, ARA (evacuation) 137.6°, ARJ (rest) 2.4cm, ARJ (evacuation) 4.0cm, H-line (rest) 7.6cm, H-line (evacuation) 8.1cm, M-line (rest) 2.6cm, M-line (evacuation) 4.2cm., Conclusions: MR-defecography is feasible in sensorimotor complete SCI patients. Individual MR-defecography findings may help to determine specific therapeutical options for respective patients suffering from severe NBD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Objective: The course of central and peripheral motor recovery after cervical spinal cord injury (SCI) may be investigated by electrophysiological measures. The goal of this study was to compare the 2 over the first year after injury in relation to motor gains., Methods: Compound motor action potentials (CMAPs), motor-evoked potentials (MEPs), and F-waves were recorded from the abductor digiti minimi and CMAP and F-waves from abductor hallucis muscles in 305 patients at about 15 days, 1 month, 3 months, 6 months, and 12 months following an acute traumatic SCI., Results: The MEP amplitudes and F-wave persistences were lower with more severe sensorimotor impairment. They steadily increased in most subgroups within 6 months after SCI. The amplitude of the CMAPs was low for the first 3 months in the most severely affected participants. This was also found for CMAPs from tibial nerve originating well below the cervical lesion level. Improvement in neurophysiological parameters correlated with improved upper extremity motor scores., Conclusion: The results point to a systematic interrelation of corticospinal transmission, spinal motoneuron excitability, and its axon function, respectively. Electrophysiological correlates of neural excitability show distinct spatial and temporal interrelations within central and peripheral motor pathways following acute cervical SCI. A strong secondary deterioration within the peripheral motor system with incomplete or no recovery depends on anatomical distance caudal to lesion and on lesion severity. Electrophysiological assessments may increase the sensitivity of interventional studies in addition to clinical measures.