Quality Control of Motor Unit Number Index (MUNIX) Measurements in 6 Muscles in a Single-Subject “Round-Robin” Setup

Background Motor Unit Number Index (MUNIX) is a neurophysiological measure that provides an index of the number of lower motor neurons in a muscle. Its performance across centres in healthy subjects and patients with Amyotrophic Lateral Sclerosis (ALS) has been established, but inter-rater variability between multiple raters in one single subject has not been investigated. Objective To assess reliability in a set of 6 muscles in a single subject among 12 examiners (6 experienced with MUNIX, 6 less experienced) and to determine variables associated with variability of measurements. Methods Twelve raters applied MUNIX in six different muscles (abductor pollicis brevis (APB), abductor digiti minimi (ADM), biceps brachii (BB), tibialis anterior (TA), extensor dig. brevis (EDB), abductor hallucis (AH)) twice in one single volunteer on consecutive days. All raters visited at least one training course prior to measurements. Intra- and inter-rater variability as determined by the coefficient of variation (COV) between different raters and their levels of experience with MUNIX were compared. Results Mean intra-rater COV of MUNIX was 14.0% (±6.4) ranging from 5.8 (APB) to 30.3% (EDB). Mean inter-rater COV was 18.1 (±5.4) ranging from 8.0 (BB) to 31.7 (AH). No significant differences of variability between experienced and less experienced raters were detected. Conclusion We provide evidence that quality control for neurophysiological methods can be performed with similar standards as in laboratory medicine. Intra- and inter-rater variability of MUNIX is muscle-dependent and mainly below 20%. Experienced neurophysiologists can easily adopt MUNIX and adequate teaching ensures reliable utilization of this method

A phase III trial of tirasemtiv as a potential treatment for amyotrophic lateral sclerosis

Objective: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) was a multinational, double-blind, randomized, placebo-controlled clinical trial. Participants tolerating 2 weeks of open-label tirasemtiv (125?mg twice daily) were randomized 3:2:2:2 to placebo or one of three target tirasemtiv dose levels, using an escalating dosage protocol lasting 28 days. The primary outcome measure was changed in slow vital capacity (SVC) at 24 weeks. Secondary endpoints included a change in muscle strength and time to respiratory milestones of disease progression. Results: Of 744 participants, 565 tolerated open-label tirasemtiv and received randomized treatment. By 24 weeks, 23 (12.2%) placebo-treated participants discontinued study treatment vs. 129 (34.2%) randomized to tirasemtiv. SVC declined by 14.4% (95% CI: ?16.8, ?11.9) in the placebo group and 13.4% (95% CI: ?15.3, ?11.6) in the tirasemtiv group (p?=?0.56). Secondary endpoints did not show significant differences. However, participants who tolerated tirasemtiv at their randomized dose showed a numeric trend toward a dose-related slowing of decline in SVC (p?=?0.11). Dizziness, fatigue, nausea, weight loss, and insomnia occurred more frequently on tirasemtiv. Serious adverse events were similar across groups. Conclusions: Tirasemtiv did not alter the decline of SVC or significantly impact secondary outcome measures. Poor tolerability of tirasemtiv may have contributed to this result. However, participants tolerating their intended dose exhibited a trend toward treatment benefit on SVC, suggesting the underlying mechanism of action may still hold promise, as is being tested with a different fast skeletal muscle troponin activator (NCT03160898)

Messenger RNA Oxidation Occurs Early in Disease Pathogenesis and Promotes Motor Neuron Degeneration in ALS

BACKGROUND: Accumulating evidence indicates that RNA oxidation is involved in a wide variety of neurological diseases and may be associated with neuronal deterioration during the process of neurodegeneration. However, previous studies were done in postmortem tissues or cultured neurons. Here, we used transgenic mice to demonstrate the role of RNA oxidation in the process of neurodegeneration. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that messenger RNA (mRNA) oxidation is a common feature in amyotrophic lateral sclerosis (ALS) patients as well as in many different transgenic mice expressing familial ALS-linked mutant copper-zinc superoxide dismutase (SOD1). In mutant SOD1 mice, increased mRNA oxidation primarily occurs in the motor neurons and oligodendrocytes of the spinal cord at an early, pre-symptomatic stage. Identification of oxidized mRNA species revealed that some species are more vulnerable to oxidative damage, and importantly, many oxidized mRNA species have been implicated in the pathogenesis of ALS. Oxidative modification of mRNA causes reduced protein expression. Reduced mRNA oxidation by vitamin E restores protein expression and partially protects motor neurons. CONCLUSION/SIGNIFICANCE: These findings suggest that mRNA oxidation is an early event associated with motor neuron deterioration in ALS, and may be also a common early event preceding neuron degeneration in other neurological diseases

Supportive and symptomatic management of amyotrophic lateral sclerosis

The main aims in the care of individuals with amyotrophic lateral sclerosis (ALS) are to minimize morbidity and maximize quality of life. Although no cure exists for ALS, supportive and symptomatic care provided by a specialist multidisciplinary team can improve survival. The basis for supportive management is shifting from expert consensus guidelines towards an evidence-based approach, which encourages the use of effective treatments and could reduce the risk of harm caused by ineffective or unsafe interventions. For example, respiratory support using noninvasive ventilation has been demonstrated to improve survival and quality of life, whereas evidence supporting other respiratory interventions is insufficient. Increasing evidence implicates a causal role for metabolic dysfunction in ALS, suggesting that optimizing nutrition could improve quality of life and survival. The high incidence of cognitive dysfunction and its impact on prognosis is increasingly recognized, although evidence for effective treatments is lacking. A variety of strategies are used to manage the other physical and psychological symptoms, the majority of which have yet to be thoroughly evaluated. The need for specialist palliative care throughout the disease is increasingly recognized. This Review describes the current approaches to symptomatic and supportive care in ALS and outlines the current guidance and evidence for these strategies