Two phase 3, multicenter, randomized, placebo-controlled clinical trials of fampridine-SR for treatment of spasticity in chronic spinal cord injury.

STUDY DESIGN: Two randomized, double-blind, placebo-controlled trials. OBJECTIVE: To evaluate the efficacy and safety of fampridine sustained-release tablets (fampridine-SR) 25 mg twice daily for moderate-to-severe spasticity in patients with chronic spinal cord injury (SCI). SETTING: United States and Canada. METHODS: Patients with incomplete chronic SCI were randomized to twice daily fampridine-SR 25 mg or placebo, with a 2-week single-blind placebo run-in, a 2-week titration, 12 weeks of stable dosing, 2 weeks of downward titration and 2 weeks of untreated follow-up. Co-primary end points were the change from baseline, averaged over the double-blind treatment period, for Ashworth score (bilateral knee flexors and extensors) and a 7-point Subject Global Impression of treatment (SGI; 1, terrible; 7, delighted). Secondary end points were: Penn Spasm Frequency Scale; the motor/sensory score from the International Standards for Neurological Classification of SCI; Clinician's Global Impression of Change of neurological status; and the International Index of Erectile Function (men) or the Female Sexual Function Index (women). RESULTS: The populations were 212 and 203 patients in the two studies, respectively. Changes from baseline in Ashworth score were -0.15 (placebo) and -0.19 (fampridine-SR) in the first study, and -0.16 (placebo) and -0.28 (fampridine-SR) in the second study. The between-treatment difference was not significant for either the Ashworth score or the SGI and, with few exceptions, neither were the secondary end points. Fampridine-SR was generally well tolerated; treatment-emergent adverse events (TEAEs) and serious TEAEs were reported with similar frequency between treatments. CONCLUSION: Fampridine-SR was well tolerated. No significant differences were observed between treatment groups for the primary end points of Ashworth score and SGI.

Walking Index for Spinal Cord Injury version II in acute spinal cord injury: reliability and reproducibility.

STUDY DESIGN: Administration of the walking index for SCI (WISCI) II is recommended to assess walking in spinal cord injury (SCI) patients. Determining the reliability and reproducibility of the WISCI II in acute SCI would be invaluable. OBJECTIVES: The objective of this study is to assess the reliability and reproducibility of the WISCI II in patients with traumatic, acute SCI. DESIGN: Test-retest analysis and calculation of reliability and smallest real difference (SRD). SETTING: SCI unit of a rehabilitation hospital. METHODS: Thirty-three patients, median age 44 years, median time since onset of SCI 40 days. Level: 20 cervical, 8 thoracic, 5 lumbar; ASIA (American Spinal Injury Association) impairment scale (AIS) grade: 32 D/1 C. Assessment of maximum WISCI II levels by two trained, blinded raters to evaluate interrater (IRR) and intrarater reliability. RESULTS: The intrarater reliability was 0.999 for therapists A and 0.979 for therapists B, for the maximum WISCI II level. The IRR for the maximum WISCI II score was 0.996 on day 1 and 0.975 on day 2. The SRD for the maximum WISCI II score was 1.147 for tetraplegics and 1.682 for paraplegics. These results suggest that a change of two WISCI II levels could be considered real. CONCLUSIONS: The WISCI II has high IRR and intrarater reliability and good reproducibility in the acute and subacute phase when administered by trained raters.

The Walking Index for Spinal Cord Injury (WISCI/WISCI II): nature, metric properties, use and misuse.

STUDY DESIGN: Literature review. OBJECTIVE: To critically review all publications/internet sites that have described/used the Walking Index for Spinal Cord Injury (WISCI II), as a measure of impairment of walking function after spinal cord injury (SCI), in order to identify its psychometric properties, clarify its nature, specify misuse and incorporate the findings in an updated guide. METHOD: A systematic literature search was done of Ovid MEDLINE, CINAHL, PsychINFO, Cochrane Central Register of Controlled Trials, Scopus and electronic sites using key words: WISCI or WISCI II, SCI, paraplegia/ tetraplegia/ quadriplegia and ambulation/gait/walking. Among 1235 citations retrieved, 154 relevant articles/sites were identified, classified and examined by the authors; recommendations were made based on findings. RESULTS AND DISCUSSION: The validity (face/concurrent/content/construct/convergent/criterion) and reliability of the WISCI II has been documented in clinical trials and clinical series, and considered adequate by systematic reviewers. In chronic SCI subjects, reliable determination of the maximum (as opposed to self-selected) WISCI II level requires more time and experience by the assessor. The correct use of WISCI II is clarified for testing acute/chronic phases of recovery after SCI, age of subjects, devices and settings. The WISCI II and walking speed measures may be performed simultaneously. CONCLUSION: The increased use of the WISCI II is attributed to its unique characteristics as a capacity measure of walking function and its strong metric properties. Appropriate use of the WISCI II was clarified and incorporated into a new guide for its use. Combining it with a walking speed measure needs further study.

Consumer preference in ranking walking function utilizing the walking index for spinal cord injury II.

STUDY DESIGN: Blinded rank ordering. OBJECTIVE: To determine consumer preference in walking function utilizing the walking Index for spinal cord injury II (WISCI II) in individuals with spinal cord injury (SCI)from the Canada, the Italy and the United States of America. METHOD: In all, 42 consumers with incomplete SCI (25 cervical, 12 thoracic, 5 lumbar) from Canada (12/42), Italy (14/42) and the United States of America (16/42) ranked the 20 levels of the WISCI II scale by their individual preference for walking. Subjects were blinded to the original ranking of the WISCI II scale by clinical scientists. Photographs of each WISCI II level used in a previous pilot study were randomly shuffled and rank ordered. Percentile, conjoint/cluster and graphic analyses were performed. RESULTS: All three analyses illustrated consumer ranking followed a bimodal distribution. Ranking for two levels with physical assistance and two levels with a walker were bimodal with a difference of five to six ranks between consumer subgroups (quartile analysis). The larger cluster (N=20) showed preference for walking with assistance over the smaller cluster (N=12), whose preference was walking without assistance and more devices. In all, 64% (27/42) of consumers ranked WISCI II level with no devices or braces and 1 person assistance higher than multiple levels of the WISCI II requiring no assistance. These results were unexpected, as the hypothesis was that consumers would rank independent walking higher than walking with assistance. CONCLUSION: Consumer preference for walking function should be considered in addition to objective measures in designing SCI trials that use significant improvement in walking function as an outcome measure.

Validity and reliability of the 10-m walk test and the 6-min walk test in spinal cord injury patients.

STUDY DESIGN: The 10-m walk test (10MWT) and the 6-min walk test (6MWT) have been recommended for assessment of walking in spinal cord injury (SCI) patients. The study was designed on test-retest analysis of the 10MWT and 6MWT. OBJECTIVES: The objective of this study was to assess validity/reliability of different methods of performing the tests. SETTING: The study was set at an SCI unit of a rehabilitation hospital. PATIENTS AND METHODS: A total of 37 patients; whose median age was 58.5 years (interquartile range 40-66, full range 19-77); median time since onset of SCI was 24 months (interquartile range 16.25-70.5, full range 6-109). Non-traumatic etiology in 20 out of 37 patients; level: 12C, 14T and 11L; American Spinal Injury Association Impairment Scale grade: 35D/2C. Assessment with the 10MWT (with or without dynamic start) and the 6MWT (short or long track) by two blinded raters to evaluate inter/intra-rater reliabilities. RESULTS: The 10MWT was performed in a median of 19 s (25th-75th interquartile range 13-28) with the dynamic start and of 18.4 s (25th-75th interquartile range 12.6-29.9) with the static start (P=0.092). The correlation between the results of the two methods was between 0.98 and 0.99. The inter- and intra-rater reliabilities were between 0.95 and 0.99 for both the methods. The 6MWT showed significant differences according to the track length: patients walked a median of 226.7 m (25th-75th interquartile range 123.2-319) on the longer track and of 187.6 m (25th-75th interquartile range 69.7-240.6) on the short one (P<0.001). The correlation between the results of the two methods was between 0.91 and 0.93. The inter- and intra-rater reliabilities were between 0.98 and 0.99. CONCLUSION: The 10MWT shows high inter/intra-rater reliability and shows comparable results with both dynamic and static start. The different testing conditions of the 6MWT (track/turns) results in significant differences that need standardization for use in future trials.

Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury.

STUDY DESIGN: Retrospective, longitudinal analysis of motor recovery data from individuals with cervical (C4-C7) sensorimotor complete spinal cord injury (SCI) according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). OBJECTIVES: To analyze the extent and patterns of spontaneous motor recovery over the first year after traumatic cervical sensorimotor complete SCI. METHODS: Datasets from the European multicenter study about SCI (EMSCI) and the Sygen randomized clinical trial were examined for conversion of American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade, change in upper extremity motor score (UEMS) or motor level, as well as relationships between these measures. RESULTS: There were no overall differences between the EMSCI and Sygen datasets in motor recovery patterns. After 1 year, up to 70% of subjects spontaneously recovered at least one motor level, but only 30% recovered two or more motor levels, with lesser values at intermediate time points. AIS grade conversion did not significantly influence motor level changes. At 1 year, the average spontaneous improvement in bilateral UEMS was 10-11 motor points. There was only moderate relationship between a change in UEMS and a change in cervical motor level (r(2)=0.30, P<0.05). Regardless of initial cervical motor level, most individuals recover a similar number of motor points or motor levels. CONCLUSION: Careful tracking of cervical motor recovery outcomes may provide the necessary sensitivity and accuracy to reliably detect a subtle, but meaningful treatment effect after sensorimotor complete cervical SCI. The distribution of the UEMS change may be more important functionally than the total UEMS recovered.

Outcome measures: evolution in clinical trials of neurological/functional recovery in spinal cord injury.

The need to determine the beneficial effect of the treatment of spinal cord injury (SCI) requires clearly defined standardized measures of the severity of injury and how well the function is restored. Improved neurological recovery should be linked to increased capacity to perform tasks such as walking, reaching and grasping, which results in meaningful gains in mobility and self-care. Measurements of recovery, capacity, mobility and self-care are the outcomes used to determine the benefits from the treatment and have evolved over the last century with contributions by the mentors and protégés of Sir Ludwig Guttmann, whom we honor today. Randomized clinical trials in the past 20 years have taught us many lessons as to which outcome measures have the greatest validity and reliability. The International Standards for Neurological Classification of SCI have become the clinical gold standard for measurement of severity, but would benefit from pathophysiological surrogates to better understand the mechanisms of recovery. Measurements of walking capacity have emerged as valid/reliable/responsive and upper extremity measures are in development, which help distinguish neurological improvement from rehabilitation adaptation. Performance of self-care and mobility has been linked to capacity and severity outcomes. In addition, new partnerships between clinical trial entities, professional societies, industry and federal agencies should facilitate identification of priorities and uniformity of measurement standards. Our ultimate goal is to improve the quality of life of those individuals with SCI whom we serve, but we must focus our investigative efforts carefully, systematically and rigorously as clinical scientists.

Who wants to walk? Preferences for recovery after SCI: a longitudinal and cross-sectional study.

STUDY DESIGN: Cross-sectional and longitudinal direct observation of a constrained consensus-building process in nine consumer panels and three rehabilitation professional panels. OBJECTIVES: To illustrate differences among consumer and clinician preferences for the restoration of walking function based on severity of injury, time of injury and age of the individual. SETTING: Regional Spinal Cord Center in Philadelphia, USA. METHODS: Twelve panels (consumer and clinical) came to independent consensus using the features-resource trade-off game. The procedure involves trading imagined levels of independence (resources) across different functional items (features) at different stages of recovery. RESULTS: Walking is given priority early in the game by eight out of nine consumer panels and by two out of three professional panels. The exception consumer panel (ISCI<50) moved walking later in the game, whereas the exception professional panel (rehRx) moved wheelchair early but walking much delayed. Bowel and Bladder was given primary importance in all panels. CONCLUSIONS: Walking is a high priority for recovery among consumers with spinal cord injury irrespective of severity of injury, time of injury and age at time of injury. Among professional staff, walking is also of high priority except in rehabilitation professionals.

Validation of the walking index for spinal cord injury in a US and European clinical population.

OBJECTIVE: To demonstrate the prospective construct validity of the walking index for spinal cord injury (WISCI) in US/European clinical population. DESIGN: Prospective Cohort in Denmark, Germany, Italy and the USA. PARTICIPANTS/METHOD: Participants with acute complete/incomplete (ASIA Impairment Scale (AIS) A, B, C and D) traumatic spinal cord injuries were enrolled from four centers. Lower extremity motor scores (LEMS), WISCI level and Locomotor Functional Independence Measure (LFIM) levels were assessed with change in ambulatory status. WISCI progression was assessed for monotonic direction of improvement (MDI). LEMS were correlated to WISCI/LFIM. Use of walking aids/braces were analyzed. RESULTS: One hundred and seventy participants were enrolled and 20 excluded. Of the 150 participants (USA 112/150; Europe 38/150) (AIS A=59, B=19, C=32, D=40), LEMS and WISCI assessments were performed initially and at final assessment (3-12 months post injury) or until maximum WISCI score of 20. Eighty-five percent of motor complete (66/78) and 10% (7/72) of motor incomplete participants showed no progression (73/150). Of the remaining participants (77/150) who improved, 81% (62/77) showed MDI. However, the deviation from MDI occurred only at one time-point in 10/15 participants. LEMS correlated with WISCI at initial and final assessment (0.47 and 0.91 P<0.001). Parallel bar use differed between the US and Europe possibly due to patterns of care. Use of braces also differed. CONCLUSION: The results support the hierarchical ranking of the WISCI scale and the correlation of WISCI levels to impairment (LEMS) in a clinical setting of four nations. Differences in practice between the US and Europe need consideration in design of trials.

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the fourth of four papers. Here, we examine the phases of a clinical trial program, the elements, types, and protocols for valid clinical trial design. The most rigorous and valid SCI clinical trial would be a prospective double-blind randomized control trial utilizing appropriate placebo control subjects. However, in specific situations, it is recognized that other trial procedures may have to be considered. We review the strengths and limitations of the various types of clinical trials with specific reference to SCI. It is imperative that the design and conduct of SCI clinical trials should meet appropriate standards of scientific inquiry to insure that meaningful conclusions about efficacy and safety can be achieved and that the interests of trial subjects are protected. We propose these clinical trials guidelines for use by the SCI clinical research community.

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics.

The International Campaign for Cures of Spinal Cord Injury Paralysis established a panel tasked with reviewing the methodology for clinical trials for spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the third of four papers. It examines inclusion and exclusion criteria that can influence the design and analysis of clinical trials in SCI, together with confounding variables and ethical considerations. Inclusion and exclusion criteria for clinical trials should consider several factors. Among these are (1) the enrollment of subjects at appropriate stages after SCI, where there is supporting data from animal models or previous human studies; (2) the severity, level, type, or size of the cord injury, which can influence spontaneous recovery rate and likelihood that an experimental treatment will clinically benefit the subject; and (3) the confounding effects of various independent variables such as pre-existing or concomitant medical conditions, other medications, surgical interventions, and rehabilitation regimens. An issue of substantial importance in the design of clinical trials for SCI is the inclusion of blinded assessments and sham surgery controls: every effort should be made to address these major issues prospectively and carefully, if clear and objective information is to be gained from a clinical trial. The highest ethical standards must be respected in the performance of clinical trials, including the adequacy and clarity of informed consent.

Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures.

An international panel reviewed the methodology for clinical trials of spinal cord injury (SCI), and provided recommendations for the valid conduct of future trials. This is the second of four papers. It examines clinical trial end points that have been used previously, reviews alternative outcome tools and identifies unmet needs for demonstrating the efficacy of an experimental intervention after SCI. The panel focused on outcome measures that are relevant to clinical trials of experimental cell-based and pharmaceutical drug treatments. Outcome measures are of three main classes: (1) those that provide an anatomical or neurological assessment for the connectivity of the spinal cord, (2) those that categorize a subject's functional ability to engage in activities of daily living, and (3) those that measure an individual's quality of life (QoL). The American Spinal Injury Association impairment scale forms the standard basis for measuring neurologic outcomes. Various electrophysiological measures and imaging tools are in development, which may provide more precise information on functional changes following treatment and/or the therapeutic action of experimental agents. When compared to appropriate controls, an improved functional outcome, in response to an experimental treatment, is the necessary goal of a clinical trial program. Several new functional outcome tools are being developed for measuring an individual's ability to engage in activities of daily living. Such clinical end points will need to be incorporated into Phase 2 and Phase 3 trials. QoL measures often do not correlate tightly with the above outcome tools, but may need to form part of Phase 3 trial measures.

Cross-cultural differences in preference for recovery of mobility among spinal cord injury rehabilitation professionals.

STUDY DESIGN: Direct observation of a constrained consensus-building process in three culturally independent five-person panels of rehabilitation professionals from the US, Italy and Canada. OBJECTIVES: To illustrate cultural differences in belief among rehabilitation professionals about the relative importance of alternative functional goals during spinal cord injury (SCI) rehabilitation. SETTING: Spinal Cord Injury Units in Philadelphia-USA, Rome-Italy and Vancouver-Canada. METHODS: Each of the three panels came to independent consensus about recovery priorities in SCI utilizing the features resource trade-off game. The procedure involves trading imagined levels of independence (resources) across different functional items (features) assuming different stages of recovery. RESULTS: Sphincter management was of primary importance to all three groups. The Italian and Canadian rehabilitation professionals, however, showed preference for walking over wheelchair mobility at lower stages of assumed recovery, whereas the US professionals set wheelchair independence at a higher priority than walking. CONCLUSIONS: These preliminary results suggest cross-cultural recovery priority differences among SCI rehabilitation professionals. These dissimilarities in preference may reflect disparities in values, cultural expectations and health care policies.

Walking index for spinal cord injury (WISCI): criterion validation.

STUDY DESIGN: Retrospective examination. OBJECTIVES: To compare the Walking Index for Spinal Cord Injury (WISCI) and current scales for their sensitivity to walking changes in subjects with a spinal cord lesion (SCL) and further validate the WISCI for use in clinical trails. SETTING: A large rehabilitation hospital in the center of Italy. PATIENTS AND METHODS: Retrospective review was performed on 284 patient records with an SCL. Measurements included neurological evaluation with Lower Extremity Motor Scores (LEMS) according to the American Spinal Injury Association (ASIA) and walking status assessed by Barthel Index (BI (0-15)), Rivermead Mobility Index (RMI (three levels)), Functional Independence Measure (FIM (1-7)), Spinal Cord Independence Measure (SCIM (0-8)), and WISCI (0-20). The WISCI is a 21-level hierarchical scale which incorporates gradations of physical assistance and devices required for walking. Improvement in walking is based on the change of scores from admission to discharge. Statistical analysis included Spearman rank correlation and chi2 test; P<0.05. RESULTS: There was a significant positive correlation between WISCI and other scales (WISCI and BI r=0.67, P<0.001; WISCI and RMI r=0.67, P<0.001; WISCI and SCIM r=0.97, P<0.001; WISCI and FIM r=0.7, P<0.001). The initial ASIA grade was predictive of mobility outcome on the WISCI: of the 78 ASIA A patients, only five achieved independent walking versus 4/17 ASIA B (P=0.02), 56/109 ASIA C (P<0.001) and 39/44 ASIA D (P<0.001). The correlation of LEMS to the WISCI was 0.58 (P<0.001). At discharge, patients were distributed into 12 WISCI levels versus four FIM, three BI, two RMI and five SCIM levels. The most frequent WISCI levels at discharge were 13 (walker, no braces or assistance), 16 (two crutches, no braces or assistance) and 20 (no devices or assistance). CONCLUSIONS: Similar correlation between the WISCI and the other scales indicates that all these measures address the same concept, mobility, which is a measure of concurrent validity. The correlation is not 100% because of conceptual differences (the WISCI incorporates gradations of physical assistance and devices required for walking while most of the other scales focus on burden of care or mobility in the environment). The WISCI is more detailed and appears more sensitive to walking recovery than the other scales, as demonstrated by our patients' score distribution at discharge. Within each of the most frequent WISCI levels (13, 16, 20) LEMS and other walking features varied; therefore the scale would benefit from further refinement based on speed, distance and energy cost.

Spinal shock revisited: a four-phase model.

Spinal shock has been of interest to clinicians for over two centuries. Advances in our understanding of both the neurophysiology of the spinal cord and neuroplasticity following spinal cord injury have provided us with additional insight into the phenomena of spinal shock. In this review, we provide a historical background followed by a description of a novel four-phase model for understanding and describing spinal shock. Clinical implications of the model are discussed as well.

Effects on age on spinal cord lesion patients' rehabilitation.

STUDY DESIGN: The present study was undertaken to focus the age-related characteristics of a population of traumatic and nontraumatic spinal cord patients. OBJECTIVES: to examine demographic, injury and outcome characteristics of older adults with spinal cord lesions as a result of trauma and nontrauma, and to compare these characteristics with those of younger patients in matched cohorts. SETTING: Spinal Cord Unit, Fondazione Santa Lucia IRCCS, a large rehabilitation hospital of the centre-south of Italy. METHODS: In total, 284 consecutive newly injured patients with traumatic and nontraumatic spinal cord lesions were retrospectively reviewed and divided according to age into two groups: under 50 years (group 1) and over 50 years (group 2). The following information was collected: onset of lesion to admission; injury variables: aetiology, level, associated injuries, medical complications and surgical intervention; length of stay; American Spinal Injury Association (ASIA) impairment and motor scores; Barthel Index (BI) and Rivermead Mobility Index (RMI) to assess independence in daily living; Walking Index for Spinal Cord Injury to assess ambulation; patients destination at discharge. In a subset of 130 subjects, a block design, matching procedure was used to control for the covariant effects of injury characteristics, time from lesion and aetiology on age effects. RESULTS: In the entire group of 284 patients, older subjects had a higher probability of having incomplete tetraplegia of nontraumatic origin; they also showed a shorter length of stay and a higher rate of complications. In the matched cohorts, younger patients showed better neurologic recovery (intended as ASIA impairment grade improvement and motor scores increase), significantly higher Barthel Index and RMI at discharge, a higher level of independence in spontaneous bladder and bowel management and a higher frequency of independent walking. CONCLUSION: Older individuals with spinal cord injury and disease do well, but have a less favourable outcome in regard to walking, bladder and bowel independence than younger subjects and have more associated medical problems. Different rehabilitative strategies, therefore, are required for older subjects, which maximises the shorter length of stay and provides the necessary medical care and increased physical assistant resources following discharge.

Validating the Functional Capacity Index as a measure of outcome following blunt multiple trauma.

BACKGROUND: The validity of the Functional Capacity Index (FCI) is evaluated by examining its distributional characteristics, its correlation with other well-known measures of outcome and its ability to discriminate among persons with injuries of varying type and severity. METHODS: A telephone survey which included the FCI and the SF-36 was administered 1 year post-injury to 1240 blunt trauma patients discharged from 12 trauma centers. A subsample of 656 patients also completed the Sickness Impact Profile (SIP) by mail. RESULTS: FCI scores correlated well with the physical health subscores of the SIP and SF-36. They also correlated well with self-reported change in health status and return to work. The FCI, when compared to either the SF-36 or the SIP, however, appears to discriminate better among patients according to the presence and severity of head trauma. CONCLUSIONS: While further testing of the FCI is needed, it holds promise as a preference based measure for assessing the physical impact of trauma.