Investigación clínica en rehabilitación neurológica para clínicos / Clinical research in neurologic rehabilitation for clinicians

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Effects of loading the unaffected limb for one session of locomotor training on laboratory measures of gait in stroke.

BACKGROUND: Walking following stroke involves compensatory strategies by the unaffected leg to cope with the deficits in the hemiparetic leg. Recently, training paradigms based on the principles of task-oriented repetitive exercise have provided a valuable insight regarding the influence of restraining compensatory movements to improve motor performances. We investigated changes in the walking movements of each lower extremity after weighting the unaffected leg. METHODS: Ten individuals early after a stroke (range: 3-7 months) who were able to walk 10 m with no aids, participated to this study. Subjects were instructed to walk on a treadmill with an external mass attached around the non affected ankle during a single session. The short-term effects on gait performance were quantified by a 3D-gait analysis system before, immediately after and 20 min after the walking technique. FINDINGS: A one factor repeated measures model revealed that stroke participants significantly improved in walking speed (P<0.001), step length (P<0.01) and cadence (P<0.01). Weight-bearing on the paretic leg increased (P<0.01) along with kinematic modifications including greater hip and knee excursion. When the mass was removed, these adaptations were maintained 20 min later. INTERPRETATION: Preliminary findings suggest that even brief gait training using a treadmill with a restrictive weight placed on the distal extremity of the non-hemiplegic lower limb can improve laboratory measures of gait ability in a sample of stroke subjects. Future studies must evaluate the effect of this technique in longer-term locomotor retraining.

Comparison of speeds used for the 15.2-meter and 6-minute walks over the year after an incomplete spinal cord injury: the SCILT Trial.

BACKGROUND: Timed walking speed for 6 to 15 m and the distance walked in 2 to 12 minutes are frequently used outcome measures in rehabilitation trials, presumably reflecting different aspects of walking ability. The database from the Spinal Cord Injury Locomotor Trial (SCILT), which tested 2 interventions for mobility upon admission for initial rehabilitation of an incomplete traumatic spinal cord injury (SCI), was used to compare the walking speed employed for each test. METHODS: From 66 to 70 patients with upper motor neuron lesions from C-5 to T-10 performed a 15.2-m and a 6-minute walk as fast as the patient deemed safe at 3 months (end of the trial intervention) and 6 and 12 months after entry. The means, standard errors, and quartiles were calculated for the speed used for each task. RESULTS: The mean speed for the 15.2-m walk did not differ from that used for the 6-minute walk at 3 and 6 months but was significantly faster at 12 months. Differences became apparent at each assessment in patients in the highest quartiles (>1.0 m/s) for the 15.2-m walk. Their speed was from 14% to 24% higher than the speed used for the 6-minute walk. CONCLUSION: The speed of the 15.2-m walk as a measure of walking ability compared to the distance walked in 6 minutes may not represent separable domains of mobility. Differences were apparent only in the most highly functional patients, who could ambulate in the community. Any difference in the walking speed used for these 2 tasks does not make enough of a clinical distinction to encourage including both a 6-minute walk and a 15.2-m walk as outcome measures in clinical trials of locomotor interventions for SCI.

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.

Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials.

The International Campaign for Cures of Spinal Cord Injury Paralysis (ICCP) supported an international panel tasked with reviewing the methodology for clinical trials in spinal cord injury (SCI), and making recommendations on the conduct of future trials. This is the first of four papers. Here, we examine the spontaneous rate of recovery after SCI and resulting consequences for achieving statistically significant results in clinical trials. We have reanalysed data from the Sygen trial to provide some of this information. Almost all people living with SCI show some recovery of motor function below the initial spinal injury level. While the spontaneous recovery of motor function in patients with motor-complete SCI is fairly limited and predictable, recovery in incomplete SCI patients (American spinal injury Association impairment scale (AIS) C and AIS D) is both more substantial and highly variable. With motor complete lesions (AIS A/AIS B) the majority of functional return is within the zone of partial preservation, and may be sufficient to reclassify the injury level to a lower spinal level. The vast majority of recovery occurs in the first 3 months, but a small amount can persist for up to 18 months or longer. Some sensory recovery occurs after SCI, on roughly the same time course as motor recovery. Based on previous data of the magnitude of spontaneous recovery after SCI, as measured by changes in ASIA motor scores, power calculations suggest that the number of subjects required to achieve a significant result from a trial declines considerably as the start of the study is delayed after SCI. Trials of treatments that are most efficacious when given soon after injury will therefore, require larger patient numbers than trials of treatments that are effective at later time points. As AIS B patients show greater spontaneous recovery than AIS A patients, the number of AIS A patients requiring to be enrolled into a trial is lower. This factor will have to be balanced against the possibility that some treatments will be more effective in incomplete patients. Trials involving motor incomplete SCI patients, or trials where an accurate assessment of AIS grade cannot be made before the start of the trial, will require large subject numbers and/or better objective assessment methods.

The evolution of walking-related outcomes over the first 12 weeks of rehabilitation for incomplete traumatic spinal cord injury: the multicenter randomized Spinal Cord Injury Locomotor Trial.

BACKGROUND: The Spinal Cord Injury Locomotor Trial (SCILT) compared 12 weeks of step training with body weight support on a treadmill (BWSTT) that included overground practice to a defined but more conventional overground mobility intervention (CONT) in patients with incomplete traumatic SCI within 8 weeks of onset. No previous studies have reported walking-related outcomes during rehabilitation. METHODS: This single-blinded, randomized trial entered 107 American Spinal Injury Association (ASIA) C and D patients and 38 ASIA B patients with lesions between C5 and L3 who were unable to walk on admission for rehabilitation. The Functional Independence Measure (FIM-L) for walking, 15-m walking speed, and lower extremity motor score (LEMS) were collected every 2 weeks. RESULTS: No significant differences were found at entry and during the treatment phase (12-week mean FIM-L = 5, velocity = 0.8 m/s, LEMS = 35, distance walked in 6 min = 250 m). Combining the 2 arms, a FIM-L >or= 4 was achieved in < 10% of ASIA B patients, 92% of ASIA C patients, and all of ASIA D patients. Walking speed of >or= 0.6 m/s correlated with a LEMS near 40 or higher. CONCLUSIONS: Few ASIA B and most ASIA C and D patients achieved functional walking ability by the end of 12 weeks of BWSTT and CONT, consistent with the primary outcome data at 6 months. Walking-related measures assessed at 2-week intervals reveal that time after SCI is an important variable for entering patients into a trial with mobility outcomes. By about 6 weeks after entry, most patients who will recover have improved their FIM-L to >3 and are improving in walking speed. Future trials may reduce the number needed to treat by entering patients with FIM-L < 4 at > 8 weeks after onset if still graded ASIA B and at > 12 weeks if still ASIA C.

Weight-supported treadmill vs over-ground training for walking after acute incomplete SCI.

OBJECTIVE: To compare the efficacy of step training with body weight support on a treadmill (BWSTT) with over-ground practice to the efficacy of a defined over-ground mobility therapy (CONT) in patients with incomplete spinal cord injury (SCI) admitted for inpatient rehabilitation. METHODS: A total of 146 subjects from six regional centers within 8 weeks of SCI were entered in a single-blinded, multicenter, randomized clinical trial (MRCT). Subjects were graded on the American Spinal Injury Association Impairment Scale (ASIA) as B, C, or D with levels from C5 to L3 and had a Functional Independence Measure for locomotion (FIM-L) score < 4. They received 12 weeks of equal time of BWSTT or CONT. Primary outcomes were FIM-L for ASIA B and C subjects and walking speed for ASIA C and D subjects 6 months after SCI. RESULTS: No significant differences were found at entry between treatment groups or at 6 months for FIM-L (n = 108) or walking speed and distance (n = 72). In the upper motor neuron (UMN) subjects, 35% of ASIA B, 92% of ASIA C, and all ASIA D subjects walked independently. Velocities for UMN ASIA C and D subjects were not significantly different for BWSTT (1.1 +/- 0.6 m/s, n = 30) and CONT (1.1 +/- 0.7, n = 25) groups. CONCLUSIONS: The physical therapy strategies of body weight support on a treadmill and defined overground mobility therapy did not produce different outcomes. This finding was partly due to the unexpectedly high percentage of American Spinal Injury Association C subjects who achieved functional walking speeds, irrespective of treatment. The results provide new insight into disability after incomplete spinal cord injury and affirm the importance of the multicenter, randomized clinical trial to test rehabilitation strategies.

Acute implantation of an avulsed lumbosacral ventral root into the rat conus medullaris promotes neuroprotection and graft reinnervation by autonomic and motor neurons.

Trauma to the conus medullaris and cauda equina may result in autonomic, sensory, and motor dysfunctions. We have previously developed a rat model of cauda equina injury, where a lumbosacral ventral root avulsion resulted in a progressive and parallel death of motoneurons and preganglionic parasympathetic neurons, which are important for i.e. bladder control. Here, we report that an acute implantation of an avulsed ventral root into the rat conus medullaris protects preganglionic parasympathetic neurons and motoneurons from cell death as well as promotes axonal regeneration into the implanted root at 6 weeks post-implantation. Implantation resulted in survival of 44+/-4% of preganglionic parasympathetic neurons and 44+/-4% of motoneurons compared with 22% of preganglionic parasympathetic neurons and 16% of motoneurons after avulsion alone. Retrograde labeling from the implanted root at 6 weeks showed that 53+/-13% of surviving preganglionic parasympathetic neurons and 64+/-14% of surviving motoneurons reinnervated the graft. Implantation prevented injury-induced atrophy of preganglionic parasympathetic neurons and reduced atrophy of motoneurons. Light and electron microscopic studies of the implanted ventral roots demonstrated a large number of both myelinated axons (79+/-13% of the number of myelinated axons in corresponding control ventral roots) and unmyelinated axons. Although the diameter of myelinated axons in the implanted roots was significantly smaller than that of control roots, the degree of myelination was appropriate for the axonal size, suggesting normal conduction properties. Our results show that preganglionic parasympathetic neurons have the same ability as motoneurons to survive and reinnervate implanted roots, a prerequisite for successful therapeutic strategies for autonomic control in selected patients with acute conus medullaris and cauda equina injuries.

Functional rewiring of brain and spinal cord after injury: the three Rs of neural repair and neurological rehabilitation.

Gains in the use of the upper extremities and in walking after brain and spinal cord injury or stroke depend especially upon the effectiveness of spared sensorimotor nodes in the networks for motor control. Biological interventions for neural repair and motor recovery may involve strategies that replace cells or signalling molecules and stimulate the regrowth of axons. The greatest success of these interventions will depend upon the functional incorporation of spared and new cells and their processes into motor networks. The distributed and modular organization of the motor neurons of the cortex and spinal cord offer a substrate that arranges or represents particular patterns of movement, yet is highly adaptable to training. Neurological impairments and related disabilities can be reduced through rehabilitative retraining protocols that engage these critical components of the sensorimotor network to promote use-dependent adaptations and functional rewiring.

How the science and engineering of spaceflight contribute to understanding the plasticity of spinal cord injury.

Space programs support experimental investigations related to the unique environment of space and to the technological developments from many disciplines of both science and engineering that contribute to space studies. Furthermore, interactions between scientists, engineers and administrators, that are necessary for the success of any science mission in space, promote interdiscipline communication, understanding and interests which extend well beyond a specific mission. NASA-catalyzed collaborations have benefited the spinal cord rehabilitation program at UCLA in fundamental science and in the application of expertise and technologies originally developed for the space program. Examples of these benefits include: (1) better understanding of the role of load in maintaining healthy muscle and motor function, resulting in a spinal cord injury (SCI) rehabilitation program based on muscle/limb loading; (2) investigation of a potentially novel growth factor affected by spaceflight which may help regulate muscle mass; (3) development of implantable sensors, electronics and software to monitor and analyze long-term muscle activity in unrestrained subjects; (4) development of hardware to assist therapies applied to SCI patients; and (5) development of computer models to simulate stepping which will be used to investigate the effects of neurological deficits (muscle weakness or inappropriate activation) and to evaluate therapies to correct these deficiencies.