Lower extremity outcome measures: considerations for clinical trials in spinal cord injury.

STUDY DESIGN: This is a focused review article. OBJECTIVES: To identify important concepts in lower extremity (LE) assessment with a focus on locomotor outcomes and provide guidance on how existing outcome measurement tools may be best used to assess experimental therapies in spinal cord injury (SCI). The emphasis lies on LE outcomes in individuals with complete and incomplete SCI in Phase II-III trials. METHODS: This review includes a summary of topics discussed during a workshop focusing on LE function in SCI, conceptual discussion of corresponding outcome measures and additional focused literature review. RESULTS: There are a number of sensitive, accurate, and responsive outcome tools measuring both quantitative and qualitative aspects of LE function. However, in trials with individuals with very acute injuries, a baseline assessment of the primary (or secondary) LE outcome measure is often not feasible. CONCLUSION: There is no single outcome measure to assess all individuals with SCI that can be used to monitor changes in LE function regardless of severity and level of injury. Surrogate markers have to be used to assess LE function in individuals with severe SCI. However, it is generally agreed that a direct measurement of the performance for an appropriate functional activity supersedes any surrogate marker. LE assessments have to be refined so they can be used across all time points after SCI, regardless of the level or severity of spinal injury. SPONSORS: Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.

Overground walking patterns after chronic incomplete spinal cord injury show distinct response patterns to unloading.

BACKGROUND: Body weight support (BWS) is often provided to incomplete spinal cord injury (iSCI) patients during rehabilitation to enable gait training before full weight-bearing is recovered. Emerging robotic devices enable BWS during overground walking, increasing task-specificity of the locomotor training. However, in contrast to a treadmill setting, there is little information on how unloading is integrated into overground locomotion. We investigated the effect of a transparent multi-directional BWS system on overground walking patterns at different levels of unloading in individuals with chronic iSCI (CiSCI) compared to controls. METHODS: Kinematics of 12 CiSCI were analyzed at six different BWS levels from 0 to 50% body weight unloading during overground walking at 2kmh- 1 and compared to speed-matched controls. RESULTS: In controls, temporal parameters, single joint trajectories, and intralimb coordination responded proportionally to the level of unloading, while spatial parameters remained unaffected. In CiSCI, unloading induced similar changes in temporal parameters. CiSCI, however, did not adapt their intralimb coordination or single joint trajectories to the level of unloading. CONCLUSIONS: The findings revealed that continuous, dynamic unloading during overground walking results in subtle and proportional gait adjustments corresponding to changes in body load. CiSCI demonstrated diminished responses in specific domains of gait, indicating that their altered neural processing impeded the adjustment to environmental constraints. CiSCI retain their movement patterns under overground unloading, indicating that this is a viable locomotor therapy tool that may also offer a potential window on the diminished neural control of intralimb coordination.

Functional assessment of the stomatognathic system. Part 2: The role of dynamic elements of analysis.

OBJECTIVES: To review the dynamic analytical elements used in the functional assessment of the stomatognathic system, summarize the available scientific evidence, and consider interrelations with body posture and cognition. METHOD AND MATERIALS: A thorough literature search was conducted using PubMed, the Cochrane Library database, and Google Scholar. Peer-reviewed articles and literature reviews provided up-to-date information addressing three topics: (a) the available knowledge and recent evidence on the relationship between the morphologic aspects of dental/craniofacial anatomy and oral function/dysfunction, (b) mandibular dynamics, considering mobility, functional activity, and existing methodologies of analysis, and (c) a possible correlation between the stomatognathic system, body posture, and cognition. RESULTS: Modern dentistry may be regarded as a human adaptation strategy, helping to conserve healthy teeth for much longer without risking overall health. It is futile to treat patients using a mechanistic, sectorial approach that misrepresents patient behavior and requests, just as it is to affirm the absence of any structure-function relationships. However, it is also evident that there is a lack of general consensus on the precise functional assessment of the stomatognathic system, mostly due to the methodologic heterogeneity employed and the high risk of bias. Despite the abundant evidence produced with the aim of providing solid arguments to define dynamic models of functional assessment of the stomatognathic system, it is yet to become highly empirical, based as it is on operator experience in daily clinical practice. CONCLUSIONS: Further efforts from the scientific and clinical community, with the help of progress in technology, remain should this gap be filled and should substantial data on differences between pathologic and physiologic dynamic models of function be provided. Dentistry needs to employ - on a larger scale - objective, dynamic methods of analysis for the functional evaluation of the stomatognathic system, embracing concepts of "personalized medicine" and "interprofessional collaborations."

Functional assessment of the stomatognathic system. Part 1: The role of static elements of analysis.

OBJECTIVES: To review the elements of static analysis in the functional assessment of the stomatognathic system, as promoted for more than a century by gnathologists, and summarize the available scientific evidence, including anthropologic observations. METHOD AND MATERIALS: A thorough search was conducted using PubMed, the Cochrane Library database, and Google Scholar. From peer-reviewed articles and other scientific literature, up-to-date information addressing three topics was identified: (a) the anthropologic perspective with particular consideration for the role of progressive dental wear over time, (b) descriptions of gnathologic principles and evidence on their scientific validity, and (c) the methodologic inaccuracies introduced by seeking to correlate variables directly rather than allowing for causal inference. RESULTS: For decades gnathology attempted to describe a structure-function correlation within the stomatognathic system by means of a model whose principles were static and mechanistic references. No scientific validation was ever achieved, placing clinical and research consensus out of reach. CONCLUSIONS: A historical perspective helps to place the fundamentals of gnathology into context: They were conceived to solve technical difficulties but were then assumed to be physiologic stereotypes. This misconception led to a decades-long promotion of mechanistic theories to describe oral function, but the evidence available today supports a more flexible and adaptable approach. Gnathologic arguments have been relegated to become exclusively of technical relevance in oral rehabilitation.

Home-Based Virtual Reality-Augmented Training Improves Lower Limb Muscle Strength, Balance, and Functional Mobility following Chronic Incomplete Spinal Cord Injury.

Key factors positively influencing rehabilitation and functional recovery after spinal cord injury (SCI) include training variety, intensive movement repetition, and motivating training tasks. Systems supporting these aspects may provide profound gains in rehabilitation, independent of the subject's treatment location. In the present study, we test the hypotheses that virtual reality (VR)-augmented training at home (i.e., unsupervised) is feasible with subjects with an incomplete SCI (iSCI) and that it improves motor functions such as lower limb muscle strength, balance, and functional mobility. In the study, 12 chronic iSCI subjects used a home-based, mobile version of a lower limb VR training system. The system included motivating training scenarios and combined action observation and execution. Virtual representations of the legs and feet were controlled via movement sensors. The subjects performed home-based training over 4 weeks, with 16-20 sessions of 30-45 min each. The outcome measures assessed were the Lower Extremity Motor Score (LEMS), Berg Balance Scale (BBS), Timed Up and Go (TUG), Spinal Cord Independence Measure mobility, Walking Index for Spinal Cord Injury II, and 10 m and 6 min walking tests. Two pre-treatment assessment time points were chosen for outcome stability: 4 weeks before treatment and immediately before treatment. At post-assessment (i.e., immediately after treatment), high motivation and positive changes were reported by the subjects (adapted Patients' Global Impression of Change). Significant improvements were shown in lower limb muscle strength (LEMS, P = 0.008), balance (BBS, P = 0.008), and functional mobility (TUG, P = 0.007). At follow-up assessment (i.e., 2-3 months after treatment), functional mobility (TUG) remained significantly improved (P = 0.005) in contrast to the other outcome measures. In summary, unsupervised exercises at home with the VR training system led to beneficial functional training effects in subjects with chronic iSCI, suggesting that it may be useful as a neurorehabilitation tool. TRIAL REGISTRATION: Canton of Zurich ethics committee (EK-24/2009, PB_2016-00545), ClinicalTrials.gov: NCT02149186. Registered 24 April 2014.

Locomotor Recovery in Spinal Cord Injury: Insights Beyond Walking Speed and Distance.

Recovery of locomotor function after incomplete spinal cord injury (iSCI) is clinically assessed through walking speed and distance, while improvements in these measures might not be in line with a normalization of gait quality and are, on their own, insensitive at revealing potential mechanisms underlying recovery. The objective of this study was to relate changes of gait parameters to the recovery of walking speed while distinguishing between parameters that rather reflect speed improvements from factors contributing to overall recovery. Kinematic data of 16 iSCI subjects were repeatedly recorded during in-patient rehabilitation. The responsiveness of gait parameters to walking speed was assessed by linear regression. Principal component analysis (PCA) was applied on the multivariate data across time to identify factors that contribute to recovery after iSCI. Parameters of gait cycle and movement dynamics were both responsive and closely related to the recovery of walking speed, which increased by 96%. Multivariate analysis revealed specific gait parameters (intralimb shape normality and consistency) that, although less related to speed increments, loaded highly on principal component one (PC1) (58.6%) explaining the highest proportion of variance (i.e., recovery of outcome over time). Interestingly, measures of hip, knee, and ankle range of motion showed varying degrees of responsiveness (from very high to very low) while not contributing to gait recovery as revealed by PCA. The conjunct application of two analysis methods distinguishes gait parameters that simply reflect increased walking speed from parameters that actually contribute to gait recovery in iSCI. This distinction may be of value for the evaluation of interventions for locomotor recovery.

Influence of Spinal Cord Integrity on Gait Control in Human Spinal Cord Injury.

Background Clinical trials in spinal cord injury (SCI) primarily rely on simplified outcome metrics (ie, speed, distance) to obtain a global surrogate for the complex alterations of gait control. However, these assessments lack sufficient sensitivity to identify specific patterns of underlying impairment and to target more specific treatment interventions. Objective To disentangle the differential control of gait patterns following SCI beyond measures of time and distance. Methods The gait of 22 individuals with motor-incomplete SCI and 21 healthy controls was assessed using a high-resolution 3-dimensional motion tracking system and complemented by clinical and electrophysiological evaluations applying unbiased multivariate analysis. Results Motor-incomplete SCI patients showed varying degrees of spinal cord integrity (spinal conductivity) with severe limitations in walking speed and altered gait patterns. Principal component (PC) analysis applied on all the collected data uncovered robust coherence between parameters related to walking speed, distortion of intralimb coordination, and spinal cord integrity, explaining 45% of outcome variance (PC 1). Distinct from the first PC, the modulation of gait-cycle variables (step length, gait-cycle phases, cadence; PC 2) remained normal with respect to regained walking speed, whereas hip and knee ranges of motion were distinctly altered with respect to walking speed (PC 3). Conclusions In motor-incomplete SCI, distinct clusters of discretely controlled gait parameters can be discerned that refine the evaluation of gait impairment beyond outcomes of walking speed and distance. These findings are specifically different from that in other neurological disorders (stroke, Parkinson) and are more discrete at targeting and disentangling the complex effects of interventions to improve walking outcome following motor-incomplete SCI.

Preserved sensory-motor function despite large-scale morphological alterations in a series of patients with holocord syringomyelia.

Although the central nervous system has a limited capacity for regeneration after acute brain and spinal cord injuries, it can reveal extensive morphological changes. Occasionally, the formation of an extensive syrinx in the spinal cord can be observed that causes no or only limited signs of functional impairment. This condition creates a unique opportunity to evaluate the mismatch between substantial morphological changes and functional outcomes. We identified seven patients with holocord syringomyelia affecting the cervical cord following chronic traumatic thoracic/lumbar spinal cord injury (19-34 years after injury) or holocord syringomyelia of non-traumatic origin, and anatomical syrinx dimensions (length, cross-sectional area) were determined using sagittal and axial magnetic resonance imaging scans. Motor- and sensory-pathway integrity were evaluated using electrophysiological assessments (i.e., motor, dermatomal sensory, and dermatomal contact-heat [dCHEP] evoked potentials, as well as nerve conduction studies). These were specifically compared to clinical measures of upper-limb strength and grasping performance, including three-dimensional motion analysis. Despite extensive anatomical changes of the cervical cord (on average 26% reduction of residual spinal cord area and intrusion of almost the entire cervical spinal cord), a clinically relevant impairment of upper-limb motor function was absent while only subtle sensory deficits could be detected. dCHEPs revealed the highest sensitivity by disclosing impairments of spinothalamic pathways. Comparable to that of the brain, extensive anatomical changes of the spinal cord can occur with only subtle functional impairment. The time scale of slowly-emerging morphological alterations is essential to permit an enormous capacity for plasticity of the spinal cord.

Comprehensive assessment of walking function after human spinal cord injury.

Regaining any locomotor function after spinal cord injury is not only of immediate importance for affected patients but also for clinical research as it allows to investigate mechanisms underlying motor impairment and locomotor recovery. Clinical scores inform on functional outcomes that are clinically meaningful to value effects of therapy while they all lack the ability to explain underlying mechanisms of recovery. For this purpose, more elaborate recordings of walking kinematics combined with assessments of spinal cord conductivity and muscle activation patterns are required. A comprehensive assessment framework comprising of multiple complementary modalities is necessary. This will not only allow for capturing even subtle changes induced by interventions that are likely missed by standard clinical outcome measures. It will be fundamental to attribute observed changes to naturally occurring spontaneous recovery in contrast to specific changes induced by novel therapeutic interventions beyond the improvements achieved by conventional therapy.

Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates.

Experimental and clinical studies suggest that primate species exhibit greater recovery after lateralized compared to symmetrical spinal cord injuries. Although this observation has major implications for designing clinical trials and translational therapies, advantages in recovery of nonhuman primates over other species have not been shown statistically to date, nor have the associated repair mechanisms been identified. We monitored recovery in more than 400 quadriplegic patients and found that functional gains increased with the laterality of spinal cord damage. Electrophysiological analyses suggested that corticospinal tract reorganization contributes to the greater recovery after lateralized compared with symmetrical injuries. To investigate underlying mechanisms, we modeled lateralized injuries in rats and monkeys using a lateral hemisection, and compared anatomical and functional outcomes with patients who suffered similar lesions. Standardized assessments revealed that monkeys and humans showed greater recovery of locomotion and hand function than did rats. Recovery correlated with the formation of corticospinal detour circuits below the injury, which were extensive in monkeys but nearly absent in rats. Our results uncover pronounced interspecies differences in the nature and extent of spinal cord repair mechanisms, likely resulting from fundamental differences in the anatomical and functional characteristics of the motor systems in primates versus rodents. Although rodents remain essential for advancing regenerative therapies, the unique response of the primate corticospinal tract after injury reemphasizes the importance of primate models for designing clinically relevant treatments.

Intralimb coordination as a sensitive indicator of motor-control impairment after spinal cord injury.

BACKGROUND: Recovery of walking function after neurotrauma, e.g., after spinal cord injury, is routinely captured using standardized walking outcome measures of time and distance. However, these measures do not provide information on possible underlying mechanisms of recovery, nor do they tell anything about the quality of gait. Subjects with an incomplete spinal cord injury are a very heterogeneous group of people with a wide range of functional impairments. A stratification of these subjects would allow increasing sensitivity for hypothesis testing and a more targeted treatment strategy. METHODS: The gait of incomplete spinal cord injured subjects was compared to healthy control subjects by analyzing kinematic data obtained by a 3-D motion capture system. Hip-knee angle-angle plots (cyclograms) informed on the qualitative aspect of gait and the intralimb coordination. Features of the cyclogram, e.g., shape of the cyclogram, cycle-to-cycle consistency and its modulation due to changes in walking speed were discerned and used to stratify spinal cord injured subjects. RESULTS: Spinal cord injured subjects were unable to modulate their cyclogram configuration when increasing speed from slow to preferred. Their gait quality remained clearly aberrant and showed even higher deviations from normal when walking at preferred speed. Qualitative categorization of spinal cord injured subjects based on their intralimb coordination was complemented by quantitative measures of cyclogram shape comparison. DISCUSSION: Spinal cord injured subjects showed distinct distortions of intralimb coordination as well as limited modulation to changes in walking speed. The specific changes of the cyclograms revealed complementary insight in the disturbance of lower-limb control in addition to measures of time and distance and may be a useful tool for patient categorization and stratification prior to clinical trial inclusion.