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

No disponible

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.

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.

Human lumbosacral spinal cord interprets loading during stepping.

Studies suggest that the human lumbosacral spinal cord can generate steplike oscillating electromyographic (EMG) patterns, but it remains unclear to what degree these efferent patterns depend on the phasic peripheral sensory information associated with bilateral limb movements and loading. We examined the role of sensory information related to lower-extremity weight bearing in modulating the efferent motor patterns of spinal-cord-injured (SCI) subjects during manually assisted stepping on a treadmill. Four nonambulatory subjects, each with a chronic thoracic spinal cord injury, and two nondisabled subjects were studied. The level of loading, EMG patterns, and kinematics of the lower limbs were studied during manually assisted or unassisted stepping on a treadmill with body weight support. The relationships among lumbosacral motor pool activity [soleus (SOL), medial gastrocnemius (MG), and tibialis anterior (TA)], limb load, muscle-tendon length, and velocity of muscle-tendon length change were examined. The EMG mean amplitude of the SOL, MG, and TA was directly related to the peak load per step on the lower limb during locomotion. The effects on the EMG amplitude were qualitatively similar in subjects with normal, partial, or no detectable supraspinal input. Responses were most consistent in the SOL and MG at load levels of < 50% of a subject's body weight. The modulation of the EMG amplitude from the SOL and MG, both across steps and within a step, was more closely associated with limb peak load than muscle-tendon stretch or the velocity of muscle-tendon stretch. Thus stretch reflexes were not the sole source of the phasic EMG activity in flexors and extensors during manually assisted stepping in SCI subjects. The EMG amplitude within a step was highly dependent on the phase of the step cycle regardless of level of load. These data suggest that level of loading on the lower limbs provides cues that enable the human lumbosacral spinal cord to modulate efferent output in a manner that may facilitate the generation of stepping. These data provide a rationale for gait rehabilitation strategies that utilize the level of load-bearing stepping to enhance the locomotor capability of SCI subjects.

Experimental brain injury and repair.

Strategies for neurological rehabilitation after brain injury have an increasingly scientific basis, which is being built upon animal models that examine the short- and long-term consequences of an injury and that test training paradigms, drugs and biologic interventions. Damage is associated with neuronal and network changes that can be manipulated to improve outcomes. Adjustments in the synaptic strength between the neuronal assemblies that represent behaviors are a key mechanism by which motor learning and functional gains evolve. Although practice aids adaptations, early overuse of cells adjacent to the site of injury might lead to a greater focal injury. The search for relevant models for rehabilitative interventions in terms of cellular and systems alterations, physiology, anatomy, impairments, and measurable behaviors continues.

Modulation of locomotor-like EMG activity in subjects with complete and incomplete spinal cord injury.

Treadmill training with partial body weight support (BWS) is being advocated as a strategy to enhance walking in patients with spinal cord injury (SCI). Clinical reports have not examined the range of sensory inputs that might modulate electromyographic (EMG) output in the legs during training. During passive, manually assisted stepping on a treadmill with partial BWS, we found similar rhythmical EMG activity in the flexor and extensor muscles of the lower extremities in subjects who had chronic, complete thoracic spinal cord injuries and in subject who had incomplete lesions that resulted in minimal motor control and an inability to ambulate. The EMG bursts were temporally synchronized to specific phases of the step cycle, and their amplitudes and durations were modulated by varying the treadmill speed and the level of limb loading. Hip extension at the end of stance often induced involuntary hip flexion that initiated the swing phase. When the incomplete SCI subjects attempted volitional stepping, the EMG bursts in some muscles had a similar waveform but greater amplitude and duration compared to that observed during passive, assisted stepping. This suggests that, as in the model of the cat after a thoracic spinal transection, peripheral sensory inputs that are associated with rhythmical locomotion can enhance the output of lumbosacral neural circuits that contribute to step-like EMG activity, even in the absence of supraspinal descending influences. Attention should be given to optimizing the manipulation of sensory inputs during rehabilitation efforts with body weight supported treadmill training.

Motor recovery and therapeutic interventions.

Loss of motor function due to damage to nervous system is an important cause of disability among neurologically ill patient. Recent work in man and experimental animals has suggested that motor control is not only a function of cerebral cortex but also depends significantly on circuits in the spinal cord. A variety of mechanisms for natural recovery from motor paralysis have been proposed. These include dendritic sprouting, synaptogenesis, restoration of axonal transport, remyelination, unmasking of alternative pathways, removal of the effect of diaschisis, alteration in neurotransmitters and bilaterality of brain function. However in many a situations these are inadequate to provide functional independence to patients. A number of rehabilitation strategies for motor retraining have therefore been used. These are traditional exercise programs, neuromuscular re-education techniques, corrective surgical interventions, EMG biofeedback and use of pharmacological agents. More recent use of treadmill training with body weight support system and functional electrical stimulation have provided promising results. The basic underlying mechanism for the use of these strategies, their efficacy and limitations require critical evaluation. Neural transplantation may open new avenues for these patients who are incapacitated due to motor dyscontrol.

Neuroplasticity. Key to recovery after central nervous system injury.

After an injury to the central nervous system, physical and cognitive impairments and disabilities often abate. These gains may be partly mediated by mechanisms that allow reorganizing of the structure and function within gray and white matter. The potential to enhance neurologic recovery by manipulating the brain and spinal cord must now be considered in clinical practice. Today's rehabilitation routines may not encourage maximum recovery. Indeed, some commonly used physical and pharmacologic methods could inhibit the restoration of motor activities such as walking. On the other hand, therapies that use our expanding knowledge of neuroplasticity could lead to better results for patients.

Dopamine agonist treatment of antegrade amnesia from a mediobasal forebrain injury.

We studied the persistent antegrade memory impairment in a woman whose brain had been surgically impaled, leaving a 1-cm-wide mediobasal tract of encephalomalacia that extended just anterior to the septal nuclei and medial to the nucleus accumbens. In a blinded, controlled, alternating repeated-measures protocol, bromocriptine significantly improved her verbal learning, functional memory, and daily recall, perhaps by acting on neurons that had been disconnected from the ventral tegmental tract's dopaminergic inputs.