Armin Curt

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 to18 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.

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 subjects functional ability to engage in activities of daily living, and (3) those that measure an individuals 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 individuals 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.

From spinal shock to spasticity Neuronal adaptations to a spinal cord injury

Objective: To investigate the adaptational changes in excitability of spinal neuronal circuits below the level of lesion from spinal shock to spasticity in patients with spinal cord injury (SCI). Methods: More than 6 months after an acute SCI, clinical follow-up examinations were paralleled by electrophysiologic recordings with tibial nerve stimulation (M-wave, F-wave, H-reflex, and flexor reflex). Results: During spinal shock, the loss of tendon tap reflexes and flaccid muscle tone were associated with low persistence of F-waves and loss of flexor reflexes, whereas H-reflexes were already elicitable. During the transition to spasticity, the reappearance of tendon tap reflexes and muscle tone and the occurrence of spasms was associated with the recovery of F-waves and flexor reflex excitability, whereas the H-to-M ratio remained about stable over months. At later stages (2 to 6 months after SCI) when clinical signs of spasticity became established, the electrophysiologic measures showed little change. In paraplegic patients, in contrast to tetraplegic patients, M-wave and flexor reflex amplitudes even decreased. Conclusions: The late decrease in M-wave and flexor reflex amplitude in paraplegic patients suggests a secondary impairment/degeneration of premotoneuronal circuits and of motoneurons. The divergent course of clinical signs of spasticity and their probable neuronal correlates indicates the occurrence of non-neuronal changes contributing to spasticity.

Corticospinal input in human gait: modulation of magnetically evoked motor responses

Abstract Transcranial magnetic stimulation (TMS) of the motor cortex was applied during locomotion to investigate the significance of corticospinal input upon the gait pattern. Evoked motor responses (EMR) were studied in the electromyogram (EMG) of tibialis anterior (TA), gastrocnemius (GM) and, for reference, abductor digiti minimi (AD) muscles by applying below-threshold magnetic stimuli during treadmill walking in healthy adults. Averages of 15 stimuli introduced randomly at each of 16 phases of the stride cycle were analysed. Phase-dependent amplitude modulation of EMR was present in TA and GM which did not always parallel the gait-associated modulation of the EMG activity. No variation of onset latency of the EMR was observed. The net modulatory response was calculated by comparing EMR amplitudes during gait with EMR amplitudes obtained (at corresponding background EMG activities) during tonic voluntary muscle contraction. Large net responses in both muscles occurred prior to or during phasic changes of EMG activity in the locomotor pattern. This facilitation of EMR was significantly higher in leg flexor than extensor muscles, with maxima in TA prior to and during late swing phase. A comparison of this facilitation of TA EMR prior to swing phase and prior to a phasic voluntary foot dorsiflexion revealed a similar onset but an increased amount of early facilitation in the gait condition. The modulated facilitation of EMR during locomotion could in part be explained by spinal effects which are different under dynamic and static motor conditions. However, we suggest that changes in corticospinal excitability during gait are also reflected in this facilitation. This suggestion is based on: (1) the similar onset yet dissimilar size of facilitatory effects in TA EMR prior to the swing phase of the stride cycle and during a voluntary dynamic activation, (2) the inverse variation of EMR and EMG amplitudes during this phase, and (3) the occurrence of this inversion at stimulation strengths below motor threshold (motor threshold was determined during weak tonic contraction and EMR were facilitated during gait). It is hypothesized that the facilitation is phase linked to ensure postural stability and is most effective during the phases prior to and during rhythmical activation of the leg muscles resulting in anticipatory adjustment of the locomotor pattern.

Three-dimensional, task-specific robot therapy of the arm after stroke: a multicentre, parallel-group randomised trial

BACKGROUND Arm hemiparesis secondary to stroke is common and disabling. We aimed to assess whether robotic training of an affected arm with ARMin--an exoskeleton robot that allows task-specific training in three dimensions-reduces motor impairment more effectively than does conventional therapy. METHODS In a prospective, multicentre, parallel-group randomised trial, we enrolled patients who had had motor impairment for more than 6 months and moderate-to-severe arm paresis after a cerebrovascular accident who met our eligibility criteria from four centres in Switzerland. Eligible patients were randomly assigned (1:1) to receive robotic or conventional therapy using a centre-stratified randomisation procedure. For both groups, therapy was given for at least 45 min three times a week for 8 weeks (total 24 sessions). The primary outcome was change in score on the arm (upper extremity) section of the Fugl-Meyer assessment (FMA-UE). Assessors tested patients immediately before therapy, after 4 weeks of therapy, at the end of therapy, and 16 weeks and 34 weeks after start of therapy. Assessors were masked to treatment allocation, but patients, therapists, and data analysts were unmasked. Analyses were by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00719433. FINDINGS Between May 4, 2009, and Sept 3, 2012, 143 individuals were tested for eligibility, of whom 77 were eligible and agreed to participate. 38 patients assigned to robotic therapy and 35 assigned to conventional therapy were included in analyses. Patients assigned to robotic therapy had significantly greater improvements in motor function in the affected arm over the course of the study as measured by FMA-UE than did those assigned to conventional therapy (F=4.1, p=0.041; mean difference in score 0.78 points, 95% CI 0.03-1.53). No serious adverse events related to the study occurred. INTERPRETATION Neurorehabilitation therapy including task-oriented training with an exoskeleton robot can enhance improvement of motor function in a chronically impaired paretic arm after stroke more effectively than conventional therapy. However, the absolute difference between effects of robotic and conventional therapy in our study was small and of weak significance, which leaves the clinical relevance in question. FUNDING Swiss National Science Foundation and Bangerter-Rhyner Stiftung.

Cellular transplants in China: observational study from the largest human experiment in chronic spinal cord injury.

Background. In China, fetal brain tissue has been transplanted into the lesions of more than 400 patients with spinal cord injury (SCI). Anecdotal reports have been the only basis for assuming that the procedure is safe and effective. Objective. To compare available reports to the experiences and objective findings of patients who received pre-operative and postoperative assessments before and up to 1 year after receiving cellular implants. Methods. Independent observational study of 7 chronic SCI subjects undergoing surgery by Dr Hongyun Huang in Beijing. Assessments included lesion location by magnetic resonance imaging, protocol of the American Spinal Injury Association (ASIA), change in disability, and detailed history of the perioperative course. Results. Inclusion and exclusion criteria were not clearly defined, as subjects with myelopathies graded ASIA A through D and of diverse causes were eligible. Cell injection sites did not always correlate with the level of injury and included the frontal lobes of a subject with a high cervical lesion. Complications, including meningitis, occurred in 5 subjects. Transient postoperative hypotonicity may have accounted for some physical changes. No clinically useful sensorimotor, disability, or autonomic improvements were found. Conclusions. The phenotype and the fate of the transplanted cells, described as olfactory ensheathing cells, are unknown. Perioperative morbidity and lack of functional benefit were identified as the most serious clinical shortcomings. The procedures observed did not attempt to meet international standards for either a safety or efficacy trial. In the absence of a valid clinical trials protocol, physicians should not recommend this procedure to patients.

Recovery from a Spinal Cord Injury: Significance of Compensation, Neural Plasticity, and Repair

Clinical recovery after a lesion of the central nervous system (CNS) can be attributed to mechanisms of functional compensation, neural plasticity, and/or repair. The relative impact of each of these mechanisms after a human spinal cord injury (SCI) has been explored in a prospective European multi-center study in 460 acute traumatic SCI subjects. Functional (activities of daily living and ambulatory capacity), neurological (sensory-motor deficits), and spinal conductivity (motor- and somato-sensory evoked potentials) measures were repeatedly followed over 12 months. In accordance with previous studies, complete SCI subjects (cSCI; n = 217) improved in activities of daily living unrelated to changes of the neurological condition, while incomplete SCI subjects (iSCI; n = 243) showed a greater functional and neurological recovery. The functional recovery in iSCI subjects was not related to an improvement of spinal conductivity, as reflected in unchanged latencies of the evoked potentials. This is in line with animal studies, where spinal conductivity of damaged spinal tracts has been reported to remain unchanged. These findings support the assumption that functional recovery occurs by compensation, especially in cSCI and by neural plasticity leading to a greater improvement in iSCI. Relevant repair of damaged spinal pathways does not take place.

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.

Locomotor pattern in paraplegic patients: training effects and recovery of spinal cord function

Recent studies have shown that a locomotor pattern can be induced and utilized by paraplegic patients under conditions of body unloading using a moving treadmill. The present study investigated the behaviour of the locomotor pattern and also the relationship of its development to the spontaneous recovery of spinal cord function assessed by clinical and electrophysiological (tibial nerve somatosensory evoked potentials and motor evoked potentials) examinations. The earliest time that spinal locomotor activity could be induced was when signs of spinal shock had disappeared. This activity was distinct from spinal stretch reflex activity. In complete paraplegic patients the locomotor pattern improved spontaneously without training. This was coincident with both an increase of gastrocnemius electromyographic activity during the stance phase of gait and a decrease of body unloading. These effects reached a plateau after about 5 weeks. In complete and incomplete paraplegic patients a near linear increase of gastrocnemius electromyographic activity occurred during the stance phase of a step cycle with daily locomotor training over the whole training period of 12 weeks. This was also coincident with a significant decrease of body unloading. In contrast to this, neither clinical nor electrophysiological examination scores improved after the onset of training in both patient groups. Only in incomplete paraplegic patients was there recovery, albeit statistically insignificant, of spinal cord function according to the sensory and motor scores obtained in the neurological examination during the time period before onset of training. An improvement of locomotor function by training was also seen in patients with paraplegia due to a cauda lesion. Such training effects on muscles and tendons could be separated from those on the spinal locomotor centres. The findings of this study may be relevant for the future clinical treatment of paraplegic patients.

Providing the clinical basis for new interventional therapies: refined diagnosis and assessment of recovery after spinal cord injury

Today, there is accumulating evidence from animal experiments that axonal regeneration and an enhanced level of functional repair can be induced after a spinal cord injury (SCI). Consequently, in the near future, new therapeutic approaches will be developed for the treatment of patients with SCI. The aim of the project presented here is to provide the required clinical basis for the implementation of novel interventional therapies. Refined and combined clinical and neurophysiological measures are needed for a precise qualitative and quantitative assessment of spinal cord function in patients with SCI at an early stage. This represents a basic requirement to recognise any improvement in the recovery of function and to monitor any significant effect of a new treatment. To this aim, five European Spinal Cord Injury Centres involved in the rehabilitation of acute SCI patients have built up a close clinical collaboration to develop a standardised protocol for the assessment of the outcome after SCI and the extent of recovery achieved by actually applied therapies in a larger population of SCI patients. The projects aim is to establish objective, refined tools as a basis for monitoring the effects of new treatment strategies.