Lateral Sclerosis Functional Rating Scale Research Articles

A 40-week phase 2B randomized, multicenter, double-blind, placebo-controlled study evaluating the safety and efficacy of memantine in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with no known cure, limited treatment options with minimal benefits, and significant unmet need for disease modifying therapies. This study investigated memantine's impact on ALS progression, with an additional focus on the effects of memantine on cognitive and behavioral changes associated with the disease. A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2018 to September 2020. ALS patients were enrolled in-person and remotely across 13 sites in the United States. Participants were randomized to memantine (20 mg twice daily) or placebo in a 2:1 ratio and completed 36 weeks of treatment. The primary outcome of disease progression was assessed by the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), and blood was collected for biomarker analysis. Of the 99 participants enrolled in the study, 89 were randomized to memantine or placebo (ages 24-83 years, male-to-female ratio ~3:2). Fifty-two participants completed the study treatment with no significant differences in disease progression, biomarker changes (including neurofilament light chain [NfL]), or neuropsychiatric testing noted between the groups. Initial NfL values correlated with the rate of ALSFRS-R decline. In this study, memantine did not impact ALS disease progression or neuropsychiatric symptoms. Trials with remote enrollment may help trial participation and success.

Clinical and epidemiological characteristics of amyotrophic lateral sclerosis in an Egyptian cohort.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder associated with progressive loss of motor neurons. It is a growing and underestimated disease, prompting this epidemiological study to describe the characteristics of ALS in Egyptian patients. This is a prospective hospital based study. ALS patients were recruited consecutively from Neuromuscular Unit in Ain Shams university Hospital from December 2018 to June 2023. Demographic data and disease related parameters were recorded. 203 ALS patients had a mean age of onset equal 39years and an inter quartile range IQR of (28.00-51.00). 76% of the cases were spinal onset ALS. Median disease duration was 2years with IQR of (1-4years); male to female ratio was 2.5:1; 18% of patients were familial ALS (FALS), while 19% were Juvenile ALS (JALS). Median diagnostic delay was 12 ± (6-36) months. Median Amyotrophic Lateral Sclerosis Functional Rating Scale Revised scores (ALSFRS-R) at presentation was 34.5 IQR of (26.00-40.00). Also, the mean rate of disease progression ALSFRS-R decline [points/month] was 0.76 ± 0.51. Our cohort was characterized by a younger age of onset, male predominance, more familial cases, within average Initial ALSFRS-R scores as well as diagnostic delay. Juvenile ALS patients were much more common in our population. These findings suggest an influential presence of genetic and epigenetic factors affecting the clinical phenotype of Egyptian ALS patients.

Safety and efficacy of memantine and trazodone versus placebo for motor neuron disease (MND SMART): stage two interim analysis from the first cycle of a phase 3, multiarm, multistage, randomised, adaptive platform trial

Motor neuron disease represents a group of progressive and incurable diseases that are characterised by selective loss of motor neurons, resulting in an urgent need for rapid identification of effective disease-modifying therapies. The MND SMART trial aims to test the safety and efficacy of promising interventions efficiently and definitively against a single contemporaneous placebo control group. We now report results of the stage two interim analysis for memantine and trazodone. MND SMART is an investigator-led, phase 3, double-blind, placebo-controlled, multiarm, multistage, randomised, adaptive platform trial recruiting at 20 hospital centres in the UK. Individuals older than 18 years with a confirmed diagnosis of either amyotrophic lateral sclerosis classified by the revised El Escorial criteria, primary lateral sclerosis, progressive muscular atrophy, or progressive bulbar palsy, regardless of disease duration, were eligible for screening. Participants were randomised (1:1:1) to receive oral trazodone 200 mg once a day, oral memantine 20 mg once a day, or matched placebo using a computer-generated minimisation algorithm delivered via a secure web-based system. Co-primary outcome measures were clinical functioning, measured by rate of change in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R), and survival. Comparisons were conducted in four stages, with predefined criteria for stopping at the end of stages one and two. We report interim analysis from the stage two results, which was done when 100 participants per group (excluding long survivors, defined as >8 years since diagnosis at baseline) completed a minimum of 12 months of follow-up for the candidate investigational medicinal products. The trial is registered on the European Clinical Trials Registry, 2019-000099-41, and ClinicalTrials.gov, NCT04302870, and is ongoing. Between Feb 27, 2020, and July 24, 2023 (database lock for interim analysis two), 554 people with a motor neuron disease were randomly allocated to memantine (183 [33%]), trazodone (185 [33%]), or placebo (186 [34%]). The primary interim analysis population comprised 530 participants, of whom 175 (33%) had been allocated memantine, 175 (33%) had been allocated trazodone, and 180 (34%) had been allocated placebo. Over 12 months of follow-up, the mean rate of change per month in ALSFRS-R was -0·650 for memantine, -0·625 for trazodone, and -0·655 for placebo (memantine versus placebo estimated mean difference 0·033, one-sided 90% CI lower level -0·085; one-sided p=0·36; trazodone vs placebo: 0·065, -0·051; one-sided p=0·24). The one-sided p values were both above the significance threshold of 10%, indicating that neither memantine nor trazodone groups met the criteria for continuation. There were 483 participants with at least one adverse event (145 [77%] on placebo, 170 [91%] on memantine, and 168 [90%] on trazodone). There were 88 participants with at least one serious adverse event (37 [20%] on memantine, 27 [14%] on trazodone, and 24 [13%] on placebo). A total of 11 serious adverse event led to treatment discontinuation. There was no survival difference between comparisons, with 49 deaths in the memantine group, 52 deaths in the trazodone group, and 48 deaths in the placebo group. Neither memantine nor trazodone improved efficacy outcomes compared with placebo. This result is sufficiently powered to warrant no further testing of trazodone or memantine in motor neuron disease at the doses evaluated in this study. The multiarm multistage design shows important benefits in reducing the time, cost, and participant numbers to reach a definitive result. The Euan MacDonald Centre, MND Scotland, My Name'5 Doddie Foundation, and Baillie Gifford.

Reliability and consistency of the Japanese version of the Primary Lateral Sclerosis Functional Rating Scale

BackgroundPrimary lateral sclerosis (PLS) is an extremely rare condition; therefore, to date no clinical studies have been conducted. The Primary Lateral Sclerosis Functional Rating Scale (PLSFRS) was developed in the United States of America. The PLSFRS is a crucial assessment scale for international collaborative research and future clinical trials for PLS. It is useful for evaluating medical conditions through face-to-face assessments and telephone interviews such as when a face-to-face assessment is not possible due to disasters or the burden of hospital visits. This study assessed the reliability and consistency of in-person and telephone interviews using the Japanese version of the PLSFRS.MethodsWe enrolled 19 Japanese patients who met the specific criteria for inclusion at the six collaborating institutions. The PLSFRS assessments were performed by two evaluators at defined time points and analyzed for intra-rater and inter-rater reliability and consistency between the in-person and telephone interviews.ResultsThe Japanese version of the PLSFRS was developed by a specialized company and translator, and modified to consider the Japanese lifestyle through a consensus among motor neuron specialists. The quadratic-weighted kappa coefficients for the intra-rater and the inter-rater agreement were substantial (intra-rater: 0.691-1.000, inter-rater: 0.634-1.000). Moreover, the intraclass correlation coefficient for the PLSFRS total score was 0.997 (95% confidence interval, 0.992–0.999).ConclusionsThis study provides results regarding the Japanese version of the PLSFRS intra-rater and inter-rater reliability and consistency between in-person and telephone interviews.

Different baseline functional patterns of the frontal cortex in amyotrophic lateral sclerosis patients with Corticospinal tract hyperintensity

Nearly half of the amyotrophic lateral sclerosis (ALS) patients showed hyperintensity of the corticospinal tract (CST+), yet whether brain functional pattern differs between CST+and CST- patients remains obscure. In the current study, 19 ALS CST+, 41 ALS CST- patients and 37 healthy controls (HC) underwent resting state fMRI scans. We estimated local activity and connectivity patterns via the Amplitude of Low Frequency Fluctuations (ALFF) and the Network-Based Statistic (NBS) approaches respectively. The ALS CST+patients did not differ from the CST- patients in amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R) score and disease duration. ALFF of the superior frontal gyrus (SFG) and the inferior frontal gyrus pars opercularis (OIFG) were highest in the HC and lowest in the ALS CST- patients, resulting in significant group differences (PFWE<0.05). NBS analysis revealed a frontal network consisting of connections between SFG, OIFG, orbital frontal gyrus, middle cingulate cortex and the basal ganglia, which exhibited HC>ALS CST+ > ALS CST- group differences (PFWE=0.037) as well. The ALFF of the OIFG was significantly correlated with ALSFRS-R (R=0.34, P=0.028) and mean connectivity of the frontal network was trend-wise significantly correlated with disease duration (R=-0.31, P=0.052) in the ALS CST- patients. However, these correlations were insignificant in ALS CST+patients (P values > 0.8). In conclusion, The ALS CST+patients exhibited different patterns of baseline functional activity and connectivity in the frontal cortex which may indicate a functional compensatory effect.

Analysis of the characteristics of patients with amyotrophic lateral sclerosis with neuromuscular junction dysfunction prior to motor neuron degeneration

Objective: To investigate the clinical and electrophysiological characteristics of patients with amyotrophic lateral sclerosis (ALS) with positive repetitive nerve stimulation (RNS) test results on the accessory nerve and negative needle electromyography (EMG) test results on the sternocleidomastoid with the goal to enrich the knowledge of disease progression in patients with ALS. Methods: The clinical data of 612 patients diagnosed with ALS at the Neurology Department of the First Medical Center, Chinese PLA General Hospital from June 2016 to August 2022 were collected. In total, 267 cases had undergone EMG tests on the sternocleidomastoid following a positive 3 Hz RNS test result on the accessory nerve, who were selected as the study subjects. The differences in clinical indicators were compared between RNS (+)/EMG (-) group and RNS (+)/EMG (+) group. A binomial distribution model with multiple variables was built to quantitatively analyze the major factors and their effects. Results: At the initial visit, 15.8% of patients with ALS were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid, accounting for 36.3% of RNS (+) patients. The decremental range of the 3 Hz RNS test delivered to the accessory nerve in these patients [-14% (-19%, -12%)] was lower than that in patients with RNS (+)/EMG (+) [-17% (-23%, -13%)] (P<0.05), while the ratio of upper limb onset (64.9%) and non-definite diagnosis (28.9%) were higher [54.7% and 13.5% for patients with RNS (+)/EMG (+), P<0.05]. Furthermore, the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score [40 (37, 42)], body mass index (BMI) [23.8 (22.0, 25.4) kg/m2] and forced vital capacity (FVC) [92.8% (76.6%, 103.8%)] were higher in patients with RNS(+)/EMG(+) (P<0.05). The multivariate model suggested that, in patients with RNS (+)/EMG (-), the ratio of upper limb onset to lower limb onset was 1.04, while that of upper limb onset to bulbar onset was 2.02, and that of lower limb onset to bulbar onset was 1.94. The ratio of non-definite ALS to definite ALS was 1.13. The ALSFRS-R score, BMI, and FVC had a protective contribution to the electrophysiological function of the motor neurons. The ratio of the effect size of the ALSFRS-R or BMI to that of FVC was 3.37 and 1.14, respectively. Conclusions: Patients with ALS that were 3 Hz RNS (+) on the accessory nerve and EMG (-) on the ipsilateral sternocleidomastoid had a smaller decremental range of the compound muscle action potential amplitude, and a higher proportion of upper limb onset and non-definite ALS. A higher ALSFRS-R score, BMI, and FVC have a protective effect to the electrophysiological function of motor neurons. The effect size of the ALSFRS-R score is the largest, followed by BMI and FVC.

Cardiac troponin T as a serum biomarker of respiratory impairment in amyotrophic lateral sclerosis.

Informative biomarkers are an urgent need in the management of amyotrophic lateral sclerosis. Serum cardiac troponin T is elevated in the majority of amyotrophic lateral sclerosis patients and increases with disease progression. We sought to establish the informative value of cardiac troponin T with regard to respiratory function, a major prognostic factor in amyotrophic lateral sclerosis. In this retrospective observation, we analyzed two independent hospital-based cohorts (d = discovery cohort; v = validation cohort) regarding serum cardiac troponin T (nd = 298; nv = 49), serum neurofilament light chain (nd = 117; nv = 17), and respiratory tests (nd = 93; nv = 49). Serum cardiac troponin T, in contrast to serum neurofilament levels, was associated with the respiratory domain of the revised amyotrophic lateral sclerosis functional rating scale and with pulmonary function parameters, namely forced vital capacity % (r = -0.45, p = 0.001) and slow vital capacity % (r = -0.50, p = 0.001). Serum cardiac troponin T reliably discriminated benchmarks of slow vital capacity <80% (AUC 0.73, 95% CI 0.62-0.84) and <50% (AUC 0.80, 95% CI 0.68-0.93), forced vital capacity <80% (AUC 0.72, 95% CI 0.61-0.83) and <50% (AUC 0.79, 95% CI 0.67-0.91). Our findings position cardiac Troponin T as a valuable serum biomarker in amyotrophic lateral sclerosis, complementing neurofilaments and expanding the understanding of underlying physiological mechanisms. In clinical practice, serum cardiac troponin T can flag benchmarks of compromised respiratory function.

Disturbances in Muscle Energy Metabolism in Patients with Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease type of motor neuron disorder characterized by degeneration of the upper and lower motor neurons resulting in dysfunction of the somatic muscles of the body. The ALS condition is manifested in progressive skeletal muscle atrophy and spasticity. It leads to death, mostly due to respiratory failure. Within the pathophysiology of the disease, muscle energy metabolism seems to be an important part. In our study, we used blood plasma from 25 patients with ALS diagnosed by definitive El Escorial criteria according to ALSFR-R (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) criteria and 25 age and sex-matched subjects. Aside from standard clinical biochemical parameters, we used the NMR (nuclear magnetic resonance) metabolomics approach to determine relative plasma levels of metabolites. We observed a decrease in total protein level in blood; however, despite accelerated skeletal muscle catabolism characteristic for ALS patients, we did not detect changes in plasma levels of essential amino acids. When focused on alterations in energy metabolism within muscle, compromised creatine uptake was accompanied by decreased plasma creatinine. We did not observe changes in plasma levels of BCAAs (branched chain amino acids; leucine, isoleucine, valine); however, the observed decrease in plasma levels of all three BCKAs (branched chain alpha-keto acids derived from BCAAs) suggests enhanced utilization of BCKAs as energy substrate. Glutamine, found to be increased in blood plasma in ALS patients, besides serving for ammonia detoxification, could also be considered a potential TCA (tricarboxylic acid) cycle contributor in times of decreased pyruvate utilization. When analyzing the data by using a cross-validated Random Forest algorithm, it finished with an AUC of 0.92, oob error of 8%, and an MCC (Matthew's correlation coefficient) of 0.84 when relative plasma levels of metabolites were used as input variables. Although the discriminatory power of the system used was promising, additional features are needed to create a robust discriminatory model.

Exploratory study to evaluate the acceptability of a wearable accelerometer to assess motor progression in motor neuron disease

Motor neuron disease (MND) is a rapidly progressive condition traditionally assessed using a questionnaire to evaluate physical function, the revised amyotrophic lateral sclerosis functional rating scale (ALSFRS-R). Its use can be associated with poor sensitivity in detecting subtle changes over time and there is an urgent need for more sensitive and specific outcome measures. The ActiGraph GT9X is a wearable device containing multiple sensors that can be used to provide metrics that represent physical activity. The primary aim of this study was to investigate the initial suitability and acceptability of limb-worn wearable devices to group of people with MND in Scotland. A secondary aim was to explore the preliminary associations between the accelerometer sensor data within the ActiGraph GT9X and established measures of physical function. 10 participants with MND completed a 12-week schedule of assessments including fortnightly study visits, both in-person and over videoconferencing software. Participants wore the device on their right wrist and right ankle for a series of movements, during a 6-min walking test and for a period of 24-h wear, including overnight. Participants also completed an ALSFRS-R and questionnaires on their experience with the devices. 80% of the participants found wearing these devices to be a positive experience and no one reported interference with daily living or added burden. However, 30% of the participants experienced technical issues with their devices. Data from the wearable devices correlated with established measures of physical function.

P.052 Utility of amyotrophic lateral sclerosis functional rating scale (ALSFRS) bulbar subscores for predicting need for gastrostomy tube

Background: We evaluated the utility of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) in predicting risk of gastrostomy tube (G-tube) insertion in patients with ALS. Methods: We conducted a retrospective study using the Pooled Resource Open-Access ALS Clinical Trials Database. People with ALS, at least two ALSFRS scores, and baseline swallowing subscore &gt;1 were included. G-tube outcome was defined as reaching a swallowing subscore ≤1. Predictors were ALSFRS bulbar subscores (swallowing, speech, salivation). Survival analyses estimated median time to outcome and cumulative probability of outcome within 91 days. Individuals were censored at last ALSFRS score. Results: We included 6,943 participants. Median [95% CI] time to G-tube insertion was 245 [228, 285], 562 [547, 621], and 1,268 [980, 1,926] for baseline swallowing subscores of 2, 3, and 4, respectively. Probability of G-tube insertion was associated with baseline swallowing, speech, and salivation subscores (log-rank test p &lt; 0.0001). For patients who transitioned to a swallowing subscore of 2 or 3, 18.1% [95% CI 16.1, 20.3] and 1.9% [95% CI 1.3, 2.7] required G-tube insertion within 91 days of score transition. Conclusions: ALSFRS bulbar subscores may identify patients at risk of G-tube insertion. Probability of G-tube insertion within 91 days is low if swallowing subscore ≥3.

Revisiting distinct nerve excitability patterns in patients with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease, characterized by loss of central and peripheral motor neurons. Although the disease is clinically and genetically heterogeneous, axonal hyperexcitability is a commonly observed feature that has been suggested to reflect an early pathophysiological step linked to the neurodegenerative cascade. Therefore, it is important to clarify the mechanisms causing axonal hyperexcitability and how these relate to the clinical characteristics of patients. Measures derived directly from a nerve excitability recording are frequently used as study end points, although their biophysical basis is difficult to deduce. Mathematical models can aid in the interpretation but are reliable only when applied to group-averaged recordings. Consequently, model estimates of membrane properties cannot be compared with clinical characteristics or treatment effects in individual patients, posing a considerable limitation in heterogeneous diseases, such as amyotrophic lateral sclerosis. To address these challenges, we revisited nerve excitability using a new pattern analysis-based approach (principal component analysis). We evaluated disease-specific patterns of excitability changes and established their biophysical origins. Based on the observed patterns, we developed new compound measures of excitability that facilitate the implementation of this approach in clinical settings. We found that excitability changes in amyotrophic lateral sclerosis patients (n = 161, median disease duration = 11 months) were characterized by four unique patterns compared with controls (n = 50, age and sex matched). These four patterns were best explained by changes in resting membrane potential (modulated by Na+/K+ currents), slow potassium and sodium currents (modulated by their gating kinetics) and refractory properties of the nerve. Consequently, we were able to show that altered gating of slow potassium channels was associated with, and predictive of, the rate of progression of the disease on the amyotrophic lateral sclerosis functional rating scale. Based on these findings, we designed four composite measures that capture these properties to facilitate implementation outside this study. Our findings demonstrate that changes in nerve excitability in patients with amyotrophic lateral sclerosis are dominated by four distinct patterns, each with a distinct biophysical origin. Based on this new approach, we provide evidence that altered slow potassium-channel function might play a role in the rate of disease progression. The magnitudes of these patterns, quantified using a similar approach or our new composite measures, have potential as efficient measures to study membrane properties directly in amyotrophic lateral sclerosis patients, and thus aid prognostic stratification and trial design.

Constipation in patients with motor neuron disease: A retrospective longitudinal study

BackgroundConstipation has been recently recognized as a complication associated with motor and autonomic dysfunction in patients with motor neuron disease (MND), typified by amyotrophic lateral sclerosis (ALS). However, the long-term characteristics of constipation remain unclear in patients with MND. We longitudinally investigated the prevalence and risk factors of constipation in a consecutive cohort of patients with MND. MethodsData from Japanese patients with MND enrolled in a single-center registry from June 2017 to December 2021 were retrospectively investigated. The diagnosis of ALS was based on the updated Awaji criteria, and other MND subtypes were also included. The presence or absence of constipation symptoms was determined by referring to the Rome III criteria. The clinical backgrounds and symptoms of patients with and without constipation were compared. ResultsAmong 155 consecutive patients (female, 63; age, 66.5 ± 12.4 years), 30.3% had constipation at diagnosis and 52.9% after a median follow-up of 18 months. Univariate analysis showed that female sex, use of tracheostomy and invasive ventilation, and delivery of enteral nutrition were more frequent in the constipation group. The Revised Amyotrophic Lateral Sclerosis Functional Rating Scale score was significantly lower in the constipation group, especially for the sub-items related to physical motor function. Multivariate analysis showed that the use of enteral nutrition was an independent risk of constipation, with an odds ratio of 3.69 (95% CI, 1.49–9.17; p = 0.005). ConclusionConstipation had a high prevalence in patients with MND with impaired motor function. Controlling defecation is important in patients with MND, especially during enteral nutrition.

ALSFRS-R decline rate prior to baseline is not useful for stratifying subsequent progression of functional decline

Objective One of the difficulties in developing a novel drug for patients with amyotrophic lateral sclerosis (ALS) is the significant variation in the clinical course. To control this variation, a 12-week run-in period is used in some clinical trials. Based on the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) change during the run-in period, only moderate progressors are selected in some clinical trials. Some reports showed that the ALSFRS-R progression rate was associated with survival. However, it is unclear whether the ALSFRS-R change in the run-in period is a useful prognostic factor of the ALSFRS-R change from baseline. In addition, we explore the inclusion criteria that could control the variability in ALS-function progression without setting a run-in period. Methods We utilized the Japanese and US ALS registry databases (JaCALS and PRO-ACT). Patients were classified into three populations (rapid, moderate, and slow progressors) based on the ALSFRS-R change prior to baseline. We also classified patients into three prognostic populations based on the ALSFRS-R change from baseline. We confirmed whether each of the three populations were matched with their respective three prognostic populations. Results Our data showed that the three groups classified by the ALSFRS-R change during the 12 weeks prior to baseline or by the rate of progression from onset to baseline did not accord with the three prognostic groups. Conclusions Our results showed that the ALSFRS-R change in the run-in period or from onset to baseline is not useful for stratifying subsequent progression of functional decline in clinical trials.

Risdiplam improves subjective swallowing quality in non-ambulatory adult patients with 5q-spinal muscular atrophy despite advanced motor impairment

Background5q-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.MethodsBulbar 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).ResultsSubjective 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.ConclusionsThe 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.

Accelerating drug development for amyotrophic lateral sclerosis: construction and application of a disease course model using historical placebo group data

BackgroundAmyotrophic lateral sclerosis (ALS) is an irreversible degenerative disease. Placebo-controlled randomized trials are currently the main trial design to assess the clinical efficacy of drugs for ALS treatment. The aim of this study was to establish models to quantitatively describe the course of ALS, explore influencing factors, and provide the necessary information for ALS drug development.MethodsWe conducted a comprehensive search of PubMed and the Cochrane Library Central Register for placebo-controlled trials that evaluated treatments for ALS. From these trials, we extracted the clinical and demographic characteristics of participants in the placebo group, as well as outcome data, which encompassed overall survival (OS) and Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) scores, at various time points.ResultsIn total, 47 studies involving 6118 participants were included. Disease duration and the proportion of patients receiving riluzole were identified as significant factors influencing OS in the placebo group. Specifically, the median OS was 35.5 months for a disease duration of 9 months, whereas it was 20.0 months for a disease duration of 36 months. Furthermore, for every 10% increase in the proportion of patients treated with riluzole (100 mg daily), there was an association with a median OS extension of approximately 0.4 months. The estimated time for the ALSFRS-R score in the placebo group to decrease to 50% of its maximum effect from baseline level was approximately 17.5 months, and the time to reach a plateau was about 40 months.ConclusionsThe established disease course model of the historical placebo group is valuable in the decision-making process for the clinical development of ALS drugs. It serves not only as an external control to evaluate the efficacy of the tested drug in single-arm trials but also as prior information that aids in accurately estimating the posterior distribution of the disease course in the placebo group during small-sample clinical trials.

Non-motor symptoms in motor neuron disease: prevalence, assessment and impact.

People with motor neuron disease often experience non-motor symptoms that may occur secondary to, or distinct from, motor degeneration and that may significantly reduce quality of life, despite being under-recognized and evaluated in clinical practice. Non-motor symptoms explored in this population-based study include pain, fatigue, gastrointestinal issues, poor sleep, low mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction. People registered on the Clinical Audit Research and Evaluation of motor neuron disease platform, the Scottish Motor Neuron Disease Register, were invited to complete a questionnaire on non-motor symptoms and a self-reported Amyotrophic Lateral Sclerosis Functional Rating Scale. The questionnaire comprised a pre-defined list of 11 potential non-motor symptoms, with the opportunity to list additional symptoms. A total of 120 individuals participated in this cross-sectional study, a 39% response rate of those sent questionnaires (n = 311); 99% of participants recruited (n = 120) experienced at least one non-motor symptom, with 72% (n = 120) reporting five or more. The symptoms most often reported were pain and fatigue (reported by 76% of participants, respectively). The symptoms reported to be most impactful were gastrointestinal issues (reported as 'severe' by 54% of participants who experienced them), followed by pain and problematic saliva (51%, respectively). Lower Amyotrophic Lateral Sclerosis Functional Rating Scale scores, indicating more advanced disease and being a long survivor [diagnosed over 8 years ago; Black et al. (Genetic epidemiology of motor neuron disease-associated variants in the Scottish population. Neurobiol Aging. 2017;51:178.e11-178.e20.)], were significantly associated with reporting more symptoms; 73% of respondents were satisfied with the frequency that non-motor symptoms were discussed in clinical care; 80% of participants indicated they believe evaluation of non-motor symptom is important to include as outcomes in trials, independent of their personal experience of these symptoms. The preferred method of assessment was completing questionnaires, at home. The overwhelming majority of people with motor neuron disease report non-motor symptoms and these frequently co-occur. Pain, fatigue, gastrointestinal issues, sleep, mood, anxiety, problematic saliva, apathy, emotional lability, cognitive complaints and sexual dysfunction are prevalent. People with motor neuron disease who had worse physical function and those who were long survivors were more likely to report more symptoms. Where reported, these symptoms are frequent, impactful and a priority for people with motor neuron disease in clinical care and trial design.

Remote respiratory resistance exercise training improves respiratory function in individuals with VCP multisystem proteinopathy

Valosin-containing protein (VCP) disease is an autosomal dominant multisystem proteinopathy associated with hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia. Myopathy frequently results in respiratory muscle weakness, leading to early mortality due to respiratory failure. We investigated the effects of a remotely administered inspiratory muscle training program in individuals with VCP disease. Nine adults with VCP mutation-positive familial myopathy without evidence of dementia were recruited for a 40-week remotely administered study. Baseline performance was established during the first 8 weeks, followed by 32 weeks of inspiratory muscle training. The primary outcome was maximum inspiratory pressure (MIP). The secondary and exploratory endpoints included spirometry, grip strength, Inclusion Body Myopathy Functional Rating Scale (IBMFRS), Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS), timed up and go, and six-minute walk test (6MWT). During the treatment phase, MIP increased significantly by a weekly mean of 0.392cm. H2O (p=0.023). In contrast, grip strength and ALSFRS significantly decreased by 0.088 lbs. (p=0.031) and 0.043 points (p=0.004) per week, respectively, as expected from the natural progression of this disease. A remotely administered inspiratory muscle training program is therefore feasible, safe, and well-tolerated in individuals with VCP disease and results in improved inspiratory muscle strength.

Clinical characteristic and prognosis of amyotrophic lateral sclerosis in a cohort of Thai patients

Background &amp; Objective: Clinical course and prognosis in amyotrophic lateral sclerosis (ALS) patients were highly variable. The information in the Thai population is still lacking. This study aimed to determine the clinical association with disease progression and prognostic factors in ALS in Thailand. Methods: This prospective cohort study evaluated 62 patients who has a diagnosis of ALS and followed up at Neurological Institute of Thailand between January 2014 and December 2018. These patients were classified into an alive group and a deceased group. The demographics, clinical characteristics, disease-related severity, and prognosis were analyzed. Results: Of the included patients, there were 40 male and 22 female, the median age at onset was 53.2 years. The median diagnosis time was 13.1 months and median follow-up duration was 18.5 months; 72.6% of patients presented with spinal onset ALS, and 27.4% with bulbar-onset. There were 20 deaths during follow-up, and the median survival time in the deceased cases was 14 months. Worse prognosis factors were bulbar symptoms at onset and low amyotrophic lateral sclerosis functional rating scale (ALSFRS) at diagnosis. Conclusion: The factors associated with lower survival in ALS patients were bulbar symptoms at onset and low ALSFRS at diagnosis.

Pain in patients with motor neuron disease: Variation of pain and association with disease severity, health-related quality of life and depression - A longitudinal study.

To describe levels of pain over time during disease progression in individual patients and for a total sample of patients with motor neuron disease (MND), respectively, and to examine associations between pain, disease severity, health-related quality of life (HRQOL), and depression. A prospective cohort study was conducted on 68 patients with MND, including data collected on five occasions over a period of 2 years. Pain was assessed using the Brief Pain Inventory - Short Form. Depression was assessed using the Amyotrophic Lateral Sclerosis (ALS)-Depression-Inventory (ADI-12). Disability progression was measured using the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised Version (ALSFRS-R). HRQOL was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5). Participants reported great individual variation over time. The median level of pain was 4 (min 0 and max 10). Higher levels of pain during the last 24h were associated with higher depression scores (ADI-12), poorer quality of life (ALSAQ-5), and lower reporting of fine and gross motor skills (ALSFRS-R). Baseline pain levels did not predict future values of depression and function. Individuals reporting average pain >3 experienced more hopelessness toward the future and reported higher depression scores compared with participants reporting average pain <3. Great within-individual variation of pain intensity was reported. Pain intensity was associated with depression, function and HRQOL cross-sectionally, but it did not have a strong prognostic value for future depression, function, or HRQOL. Patients with MND should be offered frequent assessment of pain and depressive symptoms in person-centered care, allowing for individualization of treatment.

Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis

Additional therapies for amyotrophic lateral sclerosis (ALS) are urgently needed. Immune-mediated complement activation may be involved in ALS pathogenesis as evidenced by the upregulation of terminal components; thus, complement inhibition could potentially slow progression. To evaluate the safety and efficacy of the terminal complement C5 inhibitor ravulizumab in adults with ALS. This double-blind, placebo-controlled, parallel-group, multinational, randomized, phase 3 clinical trial was conducted from March 30, 2020, to October 17, 2021, in 81 ALS specialty centers across 17 countries. A preplanned, unmasked, nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power of less than 10% would halt the trial. A total of 478 individuals were screened, and 96 were excluded. Inclusion criteria were weight of 40 kg or more, fulfillment of the El Escorial diagnostic criteria, and a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of -0.3 points per month. Study treatment consisted of placebo or a weight-based dose of intravenous ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment. The primary end point was change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS). A total of 382 participants were randomly assigned 2:1 to receive ravulizumab (n = 255; mean [SD] age, 58.6 [10.6] years; 94 female [36.9%] and 161 male [63.1%]) or placebo (n = 127; mean [SD] age, 58.0 [11.0] years; 58 female [45.7%] and 69 male [54.3%]). The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was -14.67 points (SE, 0.89 points; 95% CI, -16.42 to -12.91 points) for ravulizumab and -13.33 points (SE, 1.22 points; 95% CI, -15.72 to -10.93 points) for placebo, with no significant difference between the groups (mean [SE] difference, -1.34 [1.46] points; 95% CI, -4.21 to 1.53 points). Based on these data, the trial was terminated for futility. The primary analysis at week 50 showed no significant difference in CAFS between groups (mean [SE], 5.5 [10.8] points; 95% CI, -15.7 to 26.6 points; P = .61). Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (204 participants [80.0%]) and placebo (108 participants [85.0%]). This trial rapidly showed that terminal complement C5 inhibition with ravulizumab did not slow functional decline in participants with ALS and that the safety profiles of ravulizumab and placebo were similar. Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS. ClinicalTrials.gov Identifier: NCT04248465.