Rethinking phase 2 trials in amyotrophic lateral sclerosis.

There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on Phase 2 data, which then fail in Phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression is always expected.

Attrition and discontinuation in amyotrophic lateral sclerosis clinical trials: a meta-analysis.

Objectives: Attrition due to adverse events and disease progression impacts the integrity and generalizability of clinical trials. The aim of this study is to provide evidence-based estimates of attrition for clinical trials in amyotrophic lateral sclerosis (ALS), and identify study-related predictors, through a comprehensive systematic review and meta-analysis.

Methods: We systematically reviewed the literature to identify all randomized, placebo-controlled clinical trials in ALS and determined the number of patients who discontinued the study per randomized arm.

Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol.

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research.

Amyotrophic lateral sclerosis established as a multistep process across phenotypes.

Background And Purpose: Given the accepted multistep process of disease causation in amyotrophic lateral sclerosis (ALS), the present study was undertaken to determine the number of steps required for disease onset across each of the ALS phenotypes.

Methods: Clinical and demographic data were prospectively accumulated using the Australian Motor Neurone Disease Registry (2005-2016), and age-specific incidence rates were calculated. Poisson regression was utilized to assess the relationship between log age-specific incidence and log age of onset, with McFadden's R used to assess the goodness of fit of the model.

Feasibility and Reproducibility of Isokinetic Dynamometry in Children with Neuromuscular Diseases.

High-precision measurement tools are needed to measure relevant changes in strength and power in children with neuromuscular diseases. The aim of this study was to determine the feasibility (i), reproducibility (ii), and validity (iii) of isokinetic dynamometry in this population. Isometric and isokinetic knee and elbow flexion and extension were measured twice on the same day.

Acceptability and potential benefit of a self-compassion intervention for people living with amyotrophic lateral sclerosis: a mixed methods pilot study.

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. 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 ( = 20) and semi-structured interviews ( = 9).

Toward a Useful and Cost-Effective Workup in Chronic Polyneuropathy: The EXPRESS Study Protocol.

Background: Knowledge gaps exist about the usefulness and extent of blood tests and nerve conduction studies in the workup of polyneuropathy. We hypothesize that a limited workup improves costs spent on diagnostics without loss of diagnostic reliability or disadvantageous effect on treatment choice in many patients with a clinical diagnosis of chronic polyneuropathy. We aim to determine which investigations are necessary in the workup of patients with suspected chronic polyneuropathy clinically diagnosed by neurologists in an outpatient clinic and will perform an early health technology assessment.

Association Between Hypothalamic Volume and Metabolism, Cognition, and Behavior in Patients With Amyotrophic Lateral Sclerosis.

Background And Objectives: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival.

Cultivating Patient Preferences in ALS Clinical Trials: Reliability and Prognostic Value of the Patient-Ranked Order of Function.

Background And Objectives: The Patient-Ranked Order of Function (PROOF) is a novel approach to account for patient-reported preferences in the evaluation of treatments of amyotrophic lateral sclerosis (ALS). In this study, we assess the reliability and prognostic value of different sets of patient-reported preferences that can be used for the PROOF end point.

Methods: Data were obtained through online surveys over the course of 12 months using the population-based registry of the Netherlands.

Trial Participation in Neurodegenerative Diseases: Barriers and Facilitators: A Systematic Review and Meta-Analysis.

Background And Objectives: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation.

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.

Remote monitoring of amyotrophic lateral sclerosis using wearable sensors detects differences in disease progression and survival: a prospective cohort study.

Background: There is an urgent need for objective and sensitive measures to quantify clinical disease progression and gauge the response to treatment in clinical trials for amyotrophic lateral sclerosis (ALS). Here, we evaluate the ability of an accelerometer-derived outcome to detect differential clinical disease progression and assess its longitudinal associations with overall survival in patients with ALS.

Methods: Patients with ALS wore an accelerometer on the hip for 3-7 days, every 2-3 months during a multi-year observation period.

A 21-bp deletion in the complement regulator CD55 promotor region is associated with multifocal motor neuropathy and its disease course.

Background And Aims: To further substantiate the role of antibody-mediated complement activation in multifocal motor neuropathy (MMN) immunopathology, we investigated the distribution of promotor polymorphisms of genes encoding the membrane-bound complement regulators CD46, CD55, and CD59 in patients with MMN and controls, and evaluated their association with disease course.

Methods: We used Sanger sequencing to genotype five common polymorphisms in the promotor regions of CD46, CD55, and CD59 in 133 patients with MMN and 380 controls. We correlated each polymorphism to clinical parameters.

Scanxiety and quality of life around follow-up imaging in patients with unruptured intracranial aneurysms: a prospective cohort study.

Objectives: Patients with an unruptured intracranial aneurysm (UIA) may experience scanxiety around follow-up imaging. We studied the prevalence and temporal pattern of scanxiety, and compared quality of life (QoL) outcomes in patients with and without scanxiety.

Methods: We performed a prospective cohort study in a tertiary referral center in the Netherlands between October 2021 and November 2022.

A comparison between bioelectrical impedance analysis and air-displacement plethysmography in assessing fat-free mass in patients with motor neurone diseases: a cross-sectional study.

Aim: To determine the validity of bioelectrical impedance analysis (BIA) in quantifying fat-free mass (FFM) compared to air-displacement plethysmography (ADP) in patients with a motor neurone disease (MND).

Methods: FFM of 140 patients diagnosed with MND was determined by ADP using the BodPod (i.e.

Monitoring Nusinersen Treatment Effects in Children with Spinal Muscular Atrophy with Quantitative Muscle MRI.

Background: Spinal muscular atrophy (SMA) is caused by deficiency of survival motor neuron (SMN) protein. Intrathecal nusinersen treatment increases SMN protein in motor neurons and has been shown to improve motor function in symptomatic children with SMA.

Objective: We used quantitative MRI to gain insight in microstructure and fat content of muscle during treatment and to explore its use as biomarker for treatment effect.

Assessment of risk of ALS conferred by the GGGGCC hexanucleotide repeat expansion in among first-degree relatives of patients with ALS carrying the repeat expansion.

Objectives: We aimed to estimate the age-related risk of ALS in first-degree relatives of patients with ALS carrying the repeat expansion.

Methods: We included all patients with ALS carrying a 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 Effects of a Blended Care Intervention in Partners of Patients With Acquired Brain Injury - Results of the CARE4Carer Randomized Controlled Trial.

Objective: To assess effects of the CARE4Carer blended care intervention on caregiver mastery and psychosocial functioning compared with usual care in partners of patients with acquired brain injury (ABI).

Design: Multicenter randomized controlled trial.

Setting: Nine sites for rehabilitation medicine.

Enhanced low-threshold motor unit capacity during endurance tasks in patients with spinal muscular atrophy using pyridostigmine.

Objective: To investigate the electrophysiological basis of pyridostigmine enhancement of endurance performance documented earlier in patients with spinal muscular atrophy (SMA).

Methods: We recorded surface electromyography (sEMG) in four upper extremity muscles of 31 patients with SMA types 2 and 3 performing endurance shuttle tests (EST) and maximal voluntary contraction (MVC) measurements during a randomized, double blind, cross-over, phase II trial. Linear mixed effect models (LMM) were used to assess the effect of pyridostigmine on (i) time courses of median frequencies and of root mean square (RMS) amplitudes of sEMG signals and (ii) maximal RMS amplitudes during MVC measurements.

Portable fixed dynamometry enables home-based, reliable assessment of muscle strength in patients with amyotrophic lateral sclerosis: a pilot study.

Objective: 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).

Methods: 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.

Hybrid Controlled Clinical Trials Using Concurrent Registries in Amyotrophic Lateral Sclerosis: A Feasibility Study.

Hybrid designs with both randomized arms and an external control cohort preserve key features of randomization and utilize external information to augment clinical trials. In this study, we propose to leverage high-quality, patient-level concurrent registries to enhance clinical trials and illustrate the impact on trial design for amyotrophic lateral sclerosis. The proposed methodology was evaluated in a randomized, placebo-controlled clinical trial.

Frequency of euthanasia, factors associated with end-of-life practices, and quality of end-of-life care in patients with amyotrophic lateral sclerosis in the Netherlands: a population-based cohort study.

Background: Amyotrophic lateral sclerosis is a progressive and lethal neurodegenerative disease that is at the forefront of debates on regulation of assisted dying. Since 2002, when euthanasia was legally regulated in the Netherlands, the frequency of this end-of-life practice has increased substantially from 1·7% of all deaths in 1990 and 2005 to 4·5% in 2015. We aimed to investigate whether the frequency of euthanasia in patients with amyotrophic lateral sclerosis had similarly increased since 2002, and to assess the factors associated with end-of-life practices and the quality of end-of-life care in patients with this disease.

Continuous Theta-Burst Stimulation of the Contralesional Primary Motor Cortex for Promotion of Upper Limb Recovery After Stroke: A Randomized Controlled Trial.

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.