Objective To determine the prevalence and prognostic value of weight loss (WL) prior to diagnosis in patients with amyotrophic lateral sclerosis (ALS). Methods We enrolled patients diagnosed with ALS between 2010 and 2018 in a population-based setting. At diagnosis, detailed information was obtained regarding the patient’s disease characteristics, anthropological changes, ALS-related genotypes and cognitive functioning. Complete survival data were obtained. Cox proportional hazard models were used to assess the association between WL and the risk of death during follow-up. Results The data set comprised 2420 patients of whom 67.5% reported WL at diagnosis. WL occurred in 71.8% of the bulbar-onset and in 64.2% of the spinal-onset patients; the mean loss of body weight was 6.9% (95% CI 6.8 to 6.9) and 5.5% (95% CI 5.5 to 5.6), respectively (p<0.001). WL occurred in 35.1% of the patients without any symptom of dysphagia. WL is a strong independent predictor of survival, with a dose response relationship between the amount of WL and the risk of death: the risk of death during follow-up increased by 23% for every 10% increase in WL relative to body weight (HR 1.23, 95% CI 1.13 to 1.51, p<0.001). Conclusions This population-based study shows that two-thirds of the patients with ALS have WL at diagnosis, which also occurs independent of dysphagia, and is related to survival. Our results suggest that WL is a multifactorial process that may differ from patient to patient. Gaining further insight in its underlying factors could prove essential for future therapeutic measures.

Objective: After stroke, people experience difficulties with walking that lead to restrictions in participation in daily life. The purpose of this study was to examine the effect of virtual reality gait training (VRT) compared to non–virtual reality gait training (non-VRT) on participation in community-living people after stroke. Methods: In this assessor-blinded, randomized controlled trial with 2 parallel groups, people were included between 2 weeks and 6 months after stroke and randomly assigned to the VRT group or non-VRT group. Participants assigned to the VRT group received training on the Gait Real-time Analysis Interactive Lab (GRAIL), and participants assigned to the non-VRT group received treadmill training and functional gait exercises without virtual reality. Both training interventions consisted of 12 30-minute sessions during 6 weeks. The primary outcome was participation measured with the restrictions subscale of the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P) 3 months postintervention. Secondary outcomes included subjective physical functioning, functional mobility, walking ability, dynamic balance, walking activity, fatigue, anxiety and depression, falls efficacy, and quality of life. Results: Twenty-eight participants were randomly assigned to the VRT group and 27 to the non-VRT group, of whom 25 and 22 attended 75% or more of the training sessions, respectively. No significant differences between the groups were found over time for the USER-P restrictions subscale (1.23; 95% CI = −0.76 to 3.23) or secondary outcome measures. Patients’ experiences with VRT were positive, and no serious adverse events were related to the interventions. Conclusions: The effect of VRT was not statistically different from non-VRT in improving participation in community-living people after stroke. Impact: Although outcomes were not statistically different, treadmill-based VRT was a safe and well-tolerated intervention that was positively rated by people after stroke. VR training might, therefore, be a valuable addition to stroke rehabilitation. Lay Summary: VRT is feasible and was positively experienced by people after stroke. However, VRT was not more effective than non-VRT for improving walking ability and participation after stroke.

BACKGROUND: Despite improvements in acute stroke therapies and rehabilitation strategies, many stroke patients are left with long-term upper limb motor impairment. We assessed whether an inhibitory repetitive transcranial magnetic stimulation treatment paradigm started within 3 weeks after stroke onset promotes upper limb motor recovery. METHODS: We performed a single-center randomized, sham-controlled clinical trial. Patients with ischemic stroke or intracerebral hemorrhage and unilateral upper limb motor impairment were randomized to 10 daily sessions of active or sham continuous theta-burst stimulation (cTBS) of the contralesional primary motor cortex combined with standard upper limb therapy, started within 3 weeks after stroke onset. The primary outcome was the change in the Action Research Arm Test score from baseline (pretreatment) at 3 months after stroke. Secondary outcomes included the score on the modified Rankin Scale at 3 months and the length of stay at the rehabilitation center. Statistical analyses were performed using mixed models for repeated measures. RESULTS: We enrolled 60 patients between April 2017 and February 2021, of whom 29 were randomized to active cTBS and 31 to sham cTBS. One patient randomized to active cTBS withdrew consent before the intervention and was excluded from the analyses. The mean difference in the change in Action Research Arm Test score from baseline at 3 months poststroke was 9.6 points ([95% CI, 1.2–17.9]; P =0.0244) in favor of active cTBS. Active cTBS was associated with better scores on the modified Rankin Scale at 3 months (OR, 0.2 [95% CI, 0.1–0.8]; P =0.0225) and with an 18 days shorter length of stay at the rehabilitation center than sham cTBS ([95% CI, 0.0–36.4]; P =0.0494). There were no serious adverse events. CONCLUSIONS: Ten daily sessions of cTBS of the contralesional primary motor cortex combined with upper limb training, started within 3 weeks after stroke onset, promote recovery of the upper limb, reduce disability and dependence and leads to earlier discharge from the rehabilitation center. REGISTRATION: URL: https://trialsearch.who.int/ ; Unique identifier: NTR6133.

Objective To assess longitudinal patterns of muscle strength, motor function, and maximal compound muscle action potential amplitudes (CMAP_MAX) in older patients with spinal muscular atrophy (SMA), hypothesizing a continued decline of motor function parameters throughout life. Methods We measured muscle strength (Medical Research Council), motor function (Hammersmith Functional Motor Scale Expanded [HFMSE] and Motor Function Measure), and CMAP_MAX in treatment-naive patients. We used both longitudinal and cross-sectional data in mixed models to analyze natural history patterns. Results We included 250 patients with SMA types 1c through 4. Median patient age at assessment was 26.8 years, the number of assessments per patient ranged from 1 to 6. Baseline muscle strength and motor function scores differed significantly between SMA types, but annual rates of decline were largely similar and mostly linear. HFMSE floor effects were present for all patients with SMA type 1c, and adolescents and adults with types 2 and 3a. CMAP_MAX differed significantly between SMA types but did not decline significantly with increasing age. Muscle strength correlated very strongly with motor function (τ ≥ 0.8) but only moderately with CMAP_MAX (τ ≈ 0.5–0.6). Conclusion Muscle strength and motor function decline in older patients with SMA are constant without periods of slower progression or a plateau phase. The floor effects of the HFMSE preclude its use for long-term follow-up of adult patients with SMA types 1c through 3a. Muscle strength sum scores represent an alternative, feasible outcome measure for adolescent and adult patients with SMA.

Objective: The ALSFRS-R is limited by multidimensionality, which originates from the summation of various subscales. This prevents a direct comparison between patients with identical total scores. We aim to evaluate how multidimensionality affects the performance of the ALSFRS-R in clinical trials. Methods: We simulated clinical trial data with different treatment effects for the ALSFRS-R total score and its subscales (i.e. bulbar, fine motor, gross motor and respiratory). We considered scenarios where treatment reduced the rate of ALSFRS-R subscale decline either uniformly (i.e. all subscales respond identically to treatment) or non-uniformly (i.e. subscales respond differently to treatment). Two main analytical strategies were compared: (1) analyzing only the total score or (2) utilizing a subscale-based test (i.e. alternative strategy). For each analytical strategy, we calculated the empirical power and required sample size. Results: Both strategies are valid when there is no treatment benefit and provide adequate control of type 1 error. If all subscales respond identically to treatment, using the total score is the most powerful approach. As the differences in treatment responses between subscales increase, the more the total score becomes affected. For example, to detect a 40% reduction in the bulbar rate of decline with 80% power, the total score requires 1380 patients, whereas this is 336 when using the alternative strategy. Conclusions: Ignoring the multidimensional structure of the ALSFRS-R total score could have negative consequences for ALS clinical trials. We propose determining treatment benefit on a subscale level, prior to stating whether a treatment is generally effective.