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The antisense oligonucleotide nusinersen has been shown to improve trunk and limb motor function in patients with spinal muscular atrophy (SMA). Bulbar dysfunction, which is regularly present in SMA, is not captured by standard motor scores, and validated measurement instruments to assess it have not yet been established. Data on whether and how bulbar function changes under gene-based therapies in adult SMA patients are also unavailable. Here, we present data on the course of bulbar dysfunction assessed prospectively before nusinersen treatment initiation and 6 and 14 months later in 23 adult SMA patients using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R). While no improvement in bulbar scores was observed under treatment with nusinersen, the absence of a decline still implies a therapeutic effect of nusinersen on bulbar dysfunction. The results of this study aim to contribute to a standardized assessment of bulbar function in adult SMA patients, which may show therapeutic effects of gene-based therapies that are not evident from standard motor scores.

Introduction Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease with great heterogeneity. Biological prognostic markers are needed for the patients to plan future supportive treatment, palliative treatment, and end-of-life decisions. In addition, prognostic markers are greatly needed for the randomization in clinical trials. Objective This study aimed to test the ALS Functional Rating Scale-Revised (ALSFRS-R) progression rate (ΔFS) as a prognostic marker of survival in a Danish ALS cohort. Methods The ALSFRS-R score at test date in association with duration of symptoms, from the onset of symptoms until test date, (defined as ΔFS’) was calculated for 90 Danish patients diagnosed with either probable or definite sporadic ALS. Median survival time was then estimated from the onset of symptoms until primary endpoint (either death or tracheostomy). ΔFS’ was subjected to survival analysis using Cox proportional hazards modelling, log-rank test, and Kaplan-Meier survival analysis. Results and conclusions Both ΔFS’ and age was found to be strong predictors of survival of the Danish ALS cohort. Both variables are easily obtained at the time of diagnosis and could be used by clinicians and ALS patients to plan future supportive and palliative treatment. Furthermore, ΔFS’, is a simple, prognostic marker that predicts survival in the early phase of disease as well as at later stages of the disease.

Background Selection of appropriate trial endpoints and outcome measures is particularly important in rare disease and rapidly progressing disease such as amyotrophic lateral sclerosis (ALS) where the challenges to conducting clinical trials, are substantial: patient and disease heterogeneity, limited understanding of exact disease pathophysiology, and lack of robust and available biomarkers. To address these challenges in ALS, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised version (ALSFRS-R) was developed and has become a key primary endpoint in ALS clinical trials to assess functional disability and disease progression, often replacing survival as a primary outcome. However, increased understanding of the ALS disease journey and improvements in assistive technology for ALS patients have exposed issues with the ALSFRS-R, including non-linearity, multidimensionality and floor and ceiling effects that could challenge its continued utility as a primary outcome measure in ALS clinical trials. Recently, other qualitative scale measures of functioning disability have been developed to help address these issues. With this in mind, we conducted a literature search aimed at identifying both established and promising new measures for potential use in clinical trials. Methods We searched PubMed, Google, Google Scholar, and the reference sections of key studies to identify papers that discussed qualitative measures of functional status for potential use in ALS studies. We also searched clinicaltrials.gov to identify functional status and health-related quality of life (HRQoL) measures that have been used in ALS interventional studies. Results In addition to the ALSFRS-R, we identified several newer qualitative scales including ALSFRS-EX, ALS-MITOS, CNS-BFS, DALS-15, MND-DS, and ROADS. Strengths and limitations of each measure were identified and discussed, along with their potential to act as a primary or secondary outcome to assess patient functional status in ALS clinical trials. Conclusion This paper serves as a reference guide for researchers deciding which qualitative measures to use as endpoints in their ALS clinical trials to assess functional status. This paper also discusses the importance of including ALS HRQoL and ALS cognitive screens in future clinical trials to assess the value of a new ALS therapy more comprehensively.

Accelerometer-based digital measures offer a scalable and low-burden means of quantifying physical function, but existing processing algorithms may not quantify pathological gait correctly. In people living with amyotrophic lateral sclerosis (ALS), where gait patterns are slow, variable, and asymmetric, validated tools to quantify mobility are urgently needed. We proposed a step-counting algorithm designed for ankle-worn accelerometers that leverage wavelet-based decomposition to quantify heel strikes under heterogeneous gait patterns. We validated this method using five datasets comprising healthy individuals and those with ALS in controlled and semi-controlled activities, and we performed clinical validation in a free-living cohort of 305 people with ALS. We tested our method for accuracy in detecting steps and recognizing walking activity. Reference labels used for analytical validation were obtained from annotated studies or video-based ground truth. Step counting accuracy was assessed using Bland–Altman analysis while clinical validity was evaluated by comparing step counts to gross motor functioning on the ALS Functional Rating Scale-Revised (ALSFRS-R). Walking recognition was robust across walking conditions and body types; sensitivity ranged from 0.94 to 0.98, and specificity exceeded 0.95 across all evaluated datasets. The mean step counting bias was minimal (e.g., 0.44 steps), and the 95% limits of agreement were narrow (LoA = [−5.90, 5.40]) relative to reference standards, including video-annotated ground truth. Clinical validation indicated substantial differences between groups with various levels of gait impairment, e.g., participants who reported “walks with assist” on the ALSFRS-R accumulated a mean of 1283 (95% CI 1063, 1503) steps/day, while those reporting “normal” walking covered 3984 (95% CI 3537, 4432) steps/day. Our study covered analytical and clinical validation of a step-counting method developed for ankle-worn accelerometers and demonstrated its applicability to pathological gait. The method provides accurate quantification of walking activity in controlled and free-living environments, supporting its use as a digital endpoint in ALS research.

The ALS Functional Rating Scale in its revised version (ALSFRS-R) is a disease-specific severity score that reflects motor impairment and functional deterioration in people with amyotrophic lateral sclerosis (ALS). It has been widely applied in both clinical practice and ALS research. However, in Germany, several variants of the scale, each differing slightly from the others, have developed over time and are currently in circulation. This lack of uniformity potentially hampers data interpretation and may decrease item validity. Furthermore, shortcomings within the standard ALSFRS-R questions and answer options can limit the quality and conclusiveness of collected data. In a multistage consensus-building process, 18 clinical ALS experts from the German ALS/MND network analyzed the ALSFRS-R in its current form and created an adapted, annotated, and revised scale that closely adheres to the well-established standardized English version. Ten German-language variants of the ALSFRS-R were collected, three of which contained instructions for self-assessment. All of these variants were compiled and a comprehensive linguistic revision was undertaken. A short introduction was added to the resulting scale, comprising general instructions for use and explanations for each of the five reply options per item. This adapted version of the scale, named ALSFRS-R-SE (with the \"SE\" referring to \"self-explanatory\"), was carefully reviewed for language and comprehensibility, in both German and English. An adapted and annotated version of the ALSFRS-R scale was developed through a multistage consensus process. The decision to include brief explanations of specific scale items and reply options was intended to facilitate ALSFRS-R-SE assessments by both healthcare professionals and patients. Further studies are required to investigate the accuracy and utility of the ALSFRS-R-SE in controlled trials and clinical real-world settings.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative condition leading to progressive muscle weakness, atrophy, and ultimately death. Traditional ALS clinical evaluations often depend on subjective metrics, making accurate disease detection and monitoring disease trajectory challenging. To address these limitations, we developed the nQiALS toolkit, a machine learning-powered system that leverages smartphone typing dynamics to detect and track motor impairment in people with ALS. The study included 63 ALS patients and 30 age- and sex-matched healthy controls. We introduce the three core components of this toolkit: the nQiALS-Detection, which differentiated ALS from healthy typing patterns with an AUC of 0.89; the nQiALS-Progression, which separated slow and fast progression at specific thresholds with AUCs ranging between 0.65 and 0.8; and the nQiALS-Fine Motor, which identified subtle progression in fine motor dysfunction, suggesting earlier prediction than the state-of-the-art assessment. Together, these tools represent an innovative approach to ALS assessment, offering a complementary, objective metric to traditional clinical methods and which may reshape our understanding and monitoring of ALS progression.

The objective of our study was to perform a randomized controlled trial (RCT) aimed to evaluate the effects of three strictly monitored exercise programs (SMEP) compared to “usual care” (UCP) in a cohort of ALS patients. We included patients with definite and probable ALS and disease duration ≤24 months. Patients were randomized to receive a SMEPs or a UCP. SMEPs included three subgroups of treatment: active exercises associated with cycloergometer activity (1A), only active (1B) and passive (1C) exercises, respectively. Moreover, SMEP patients and their caregivers were trained to a daily home-based passive exercise program. The UCP group was treated with passive and stretching exercises twice weekly. The treatment period for both groups was 6 months (T180), and patients were assessed by revised ALS Functional Rating Scale (ALSFRS-R),  % Forced Vital Capacity (FVC %), and McGill Quality of Life (MGQoL) questionnaire. ALSFRS-R score was also evaluated at 6 months after the treatment period (T360). Sixty ALS patients were randomly assigned to one of two arms: SMEP Group included 30 patients, ten subjects for each subgroup (1A, 1B, and 1C); 30 patients were included in the UCP Group. At T180 and T360, SMEPs group had significantly higher ALSFRS-R score compared to the UCP group (32.8 ± 6.5 vs 28.7 ± 7.5, p  = 0.0298; 27.5 ± 7.6 vs 23.3 ± 7.6, p  = 0.0338, respectively). No effects of SMEPs on survival, respiratory decline and MGQol were found. In conclusion, although no effect on survival was demonstrated, our data suggest that a strictly monitored exercise program may significantly reduce motor deterioration in ALS patients.

Background 5q-associated spinal muscular atrophy (SMA) is characterized by the progressive loss of motor neurons with consecutive weakness and atrophy of the limb, respiratory, and bulbar muscles. While trunk and limb motor function improve or stabilize in adults with SMA under nusinersen and risdiplam treatment, the efficacy on bulbar function in this age group of patients remains uncertain. However, it is important to assess bulbar dysfunction, which frequently occurs in the disease course and is associated with increased morbidity and mortality. Methods Bulbar function was evaluated prospectively in 25 non-ambulatory adults with type 2 and 3 SMA before and 4 and 12 months after risdiplam treatment initiation using the Sydney Swallow Questionnaire (SSQ) and the bulbar subscore of the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (b-ALSFRS-R). Extremity function was assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). Results Subjective swallowing quality, measured with the SSQ, improved after 12 months of therapy with risdiplam. For the b-ALSFRS-R, a non-significant trend towards improvement was observed. The RULM score improved after 12 months of risdiplam therapy, but not the HFMSE score. HFMSE and RULM scores did not correlate with the SSQ but the b-ALSFRS-R score at baseline. Conclusions The improvement in subjective swallowing quality under risdiplam treatment, despite an advanced disease stage with severe motor deficits, strengthens the importance of a standardized bulbar assessment in addition to established motor scores. This may reveal relevant treatment effects and help individualize treatment decisions in the future.

Objective To validate an Italian version of the Rasch-Built Overall ALS Disability Scale (ROADS) in a broad population of patients and assess its longitudinal performance over time. Methods 270 ALS patients referring to the Motor Neuron Disease Clinic of the University of Padova and Modena (Italy) accepted to compile the Italian version of the ROADS and results were correlated with the ALSFRSr and ALSAQ-40 scores, FVC values, and creatinine or albumin blood levels. To verify test–retest reliability, patients were asked to fill in a second copy of the scale within 5–7 days. Thirty-nine patients compiled a further copy of questionnaire during the follow up visit (after 133 days on average) which allowed us a longitudinal assessment of the scale. Results We found a good external construct validity between ROADS and either ALSFRS-R (correlation coefficient = 0.85) or ALSAQ-40 (correlation coefficient = − 0.84). Test–retest reliability was excellent with a concordance-correlation coefficient of 0.93. Yet, we observed a significant correlation between changes over time of the ROADS normalised sum score (− 2.18 point loss per month) and those of both the ALSFRS-R (positive correlation; Rho = 0.64, p  ≤ 0.0001) or the ALSAQ-40 (negative correlation; Rho = − 0.60, p  = 0.014). Conclusions The Italian version of ROADS proved to be a reliable marker to monitor overall disability in ALS patients. Further studies are necessary to assess its longitudinal performance.

•PCEF and PEF significantly correlated with functional impairment.•FVC% monthly decline correlated with ALSFRS-R total, spinal sub-score and ΔFS.•sFVC% monthly decline correlated with ALSFRS-R total, bulbar sub-score and ΔFS.•Only FVC% and sFVC% revealed significant relations with survival.•Patients with both FVC% and sFVC% below their cut-offs had the worst prognosis. Amyotrophic lateral sclerosis (ALS) patients tend to develop progressive respiratory muscle weakness, leading to ventilatory failure and ineffective cough, principal causes of morbidity and mortality. Since patients are usually unaware of these symptoms, these are generally not noticed until the advanced stages and are associated with poor prognosis. The monitoring of respiratory function on a regular basis is therefore of great importance. Despite the availability of several pulmonary function tests, none of them was found to be the best indicator of the disease progression throughout the course of this condition. The main aim of our work was to evaluate the prognostic value of these respiratory measures evaluated in a brief period of observation and their correlation with motor functional impairments in an ALS cohort. Patients with ALS who had respiratory assessments performed and functional motor scales administered at baseline and six months later were included. All patients were assessed with forced vital capacity, both in seated and supine position (FVC; sFVC), peak expiratory flow (PEF), peak expiratory cough flow (PCEF), the revised ALS functional rating scale (ALSFRS-R), at baseline and after six months, and their disease progression rate (ΔFS) was obtained. We included 73 patients with probable or definite ALS according to El-Escorial revised Criteria. At baseline, PCEF and PEF significantly correlated with ALSFRS-R total, bulbar and spinal subscores and ΔFS, while FVC% significantly correlated with ΔFS. After 6 months all the respiratory parameters significantly correlated with ALSFRS-R and all its subscores. Longitudinally, FVC%, sFVC% and PCEF significantly correlated with ΔFS and some of ALSFRS-R subscores. As concerns the survival analysis, monthly declines of FVC% and sFVC%, significantly correlated with the survival. The worse prognosis in terms of survival was finally found in those whose FVC% and sFVC% dropped below their respective cut-offs. Throughout the course of ALS disease, the monitoring of several respiratory markers, namely FVC, sFVC, PEF and PCEF, plays a critical role in predicting the prognosis of these subjects, both in terms of survival and functional ability. The implementation of monthly cut-offs in the evaluation of FVC and sFVC may allow a faster recognition of those patients with worse prognosis and therefore an optimized tailored clinical care, as well as a better stratification in clinical trials.