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The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was developed more than 25 years ago as an instrument to monitor functional change over time in patients with ALS. It has since been revised and extended to meet the needs of high data quality in ALS trials (ALSFRS-R), however a full re-validation of the scale was not completed. Despite this, the scale has remained a primary outcome measure in clinical trials. We convened a group of clinical trialists to discuss and explore opportunities to improve the scale and propose alternative measures. In this meeting report, we present a call to action on the use of the ALSFRS-Revised scale in clinical trials, focusing on the need for (1) harmonization of the ALSFRS-R administration globally, (2) alignment on a set of recommendations for clinical trial design and statistical analysis plans (SAPs), and (3) use of additional outcome measures. [ABSTRACT FROM AUTHOR]

We aimed to estimate the age-related risk of ALS in first-degree relatives of patients with ALS carrying the C9orf72 repeat expansion. We included all patients with ALS carrying a C9orf72 repeat expansion in The Netherlands. Using structured questionnaires, we determined the number of first-degree relatives, their age at death due to ALS or another cause, or age at time of questionnaire. The cumulative incidence of ALS among first-degree relatives was estimated, while accounting for death from other causes. Variability in ALS risk between families was evaluated using a random effects hazards model. We used a second, distinct approach to estimate the risk of ALS and FTD in the general population, using previously published data. In total, 214 of the 2,486 (9.2%) patients with ALS carried the C9orf72 repeat expansion. The mean risk of ALS at age 80 for first-degree relatives carrying the repeat expansion was 24.1%, but ranged between individual families from 16.0 to 60.6%. Using the second approach, we found the risk of ALS and FTD combined was 28.7% (95% CI 17.8%–54.3%) for carriers in the general population. On average, our estimated risk of ALS in the C9orf72 repeat expansion was lower compared to historical estimates. We showed, however, that the risk of ALS likely varies between families and one overall penetrance estimate may not be sufficient to describe ALS risk. This warrants a tailor-made, patient-specific approach in testing. Further studies are needed to assess the risk of FTD in the C9orf72 repeat expansion. [ABSTRACT FROM AUTHOR]

To determine the feasibility, reliability, and sensitivity of remotely monitoring muscle strength loss of knee extensors using a novel portable fixed dynamometer (PFD) in patients with amyotrophic lateral sclerosis (ALS). We conducted a pilot study with a newly developed device to measure knee extension strength. Patients performed unsupervised PFD measurements, biweekly, for 6 months at home. We evaluated feasibility using adherence and a device-specific questionnaire. Reliability was assessed by (1) comparing unsupervised and supervised measurements to identify systematic bias, and (2) comparing consecutive unsupervised measurements to determine test-retest reliability expressed as intraclass correlation coefficient (ICC) and standard error of measurement (SEM). Sensitivity to detect longitudinal change was described using linear mixed-effects models. We enrolled 18 patients with ALS. Adherence was 86%, where all patients found that the device suitable to measure muscle strength at home; 4 patients (24%) found the measurements burdensome. The correlation between (un)supervised measurements was excellent (Pearson's r 0.97, 95%CI; 0.94 − 0.99) and no systematic bias was present (mean difference 0.13, 95%CI; −2.22 − 2.48, p = 0.91). Unsupervised measurements had excellent test-retest reliability with an average ICC of 0.97 (95%CI: 0.94 − 0.99) and SEM of 5.8% (95%CI: 4.8 − 7.0). Muscle strength declined monthly by 1.9 %predicted points (95%CI; −3.0 to −0.9, p = 0.001). Using the PFD, it proved feasible to perform knee extension strength measurements at home which were reliable and sensitive for detecting muscle strength loss. Larger studies are warranted to compare the device with conventional outcomes. [ABSTRACT FROM AUTHOR]

Determine vitamin B12 threshold levels below which additional testing of methylmalonic acid (MMA) and/or homocysteine (Hcy) is useful to diagnose metabolic vitamin B12 deficiency in patients with polyneuropathy, and how vitamin B12, MMA and Hcy levels relate to the effect of supplementation therapy. In a retrospective cohort study of 331 patients with polyneuropathy, vitamin B12, MMA and Hcy were measured. Linear regression models with vitamin B12 as dependent and Hcy or MMA as covariate were compared, to assess which was best related to vitamin B12. Threshold vitamin B12 levels for metabolic deficiency (defined as elevatede metabolites) were determined using logistic regression with elevated metabolites as dependent and vitamin B12 as covariate. A structured interview was conducted in 42 patients to evaluate response to vitamin B12 supplementation. MMA was best related to vitamin B12. Using elevated MMA for metabolic deficiency, we found 90% sensitivity at a vitamin B12 threshold level <264 pmol/L (358 pg/mL) and 95% sensitivity at <304 pmol/L (412 pg/mL). Improvement after supplementation was reported by 19% patients and stabilization by 24%. 88% of patients with improvement and 90% with stabilization either had absolute deficiency (Vitamin B12 < 148 pmol/L) or metabolic deficiency (elevated MMA and vitamin B12 ≥ 148 pmol/L). There were no additional patients with improvement or stabilization with isolated elevated Hcy. Testing of MMA has additional value in identifying patients with clinically relevant metabolic deficiency when vitamin B12 is below 304 pmol/L (412 pg/mL). Supplementation can be effective in patients with absolute and metabolic deficiency. [ABSTRACT FROM AUTHOR]

AbstractObjective: This proof-of-concept study aimed to explore the acceptability and potential benefit of a self-guided online self-compassion intervention to aid resilient coping and reduce emotional distress among patients and caregivers living with ALS. Methods: A single-arm pilot study was conducted in 20 adults living with ALS either as a patient or as a caregiver. Acceptability was examined using questionnaires (n = 20) and semi-structured interviews (n = 9). Potential benefit was assessed as changes in self-compassion, self-criticism and emotional distress, determined using psychological questionnaires at 3 and 6 weeks. Questionnaires were analyzed using linear mixed-effects models and interview data using inductive thematic analysis. Results: Out of 20 participants who started the intervention, 16 completed the study (80%). The majority of study completers (12/16) were satisfied with the intervention, but the data suggest room for improvement in terms of personalization. Qualitative data revealed multiple psychological benefits of using the intervention, including self-kindness, emotional self-awareness and savoring. Although not statistically significant, quantitative data showed positive trends with increased self-compassion (mean difference: 2.07; 95% CI: −.5.76 − 1.63) and reduced self-criticism (mean difference: −2.62; 95% CI: −.1.97 − 7.23) and emotional distress (mean difference: −2.49; 95% CI: −.51 − 5.50) at week 6 compared to baseline. Conclusions: The findings suggest that a self-compassion intervention is acceptable to people living with ALS, but its beneficial effects and the mechanisms involved have yet to be established in larger and more diverse samples, using controlled designs. [ABSTRACT FROM AUTHOR]