Patients with ALS show highly correlated progression rates in left and right limb muscles

Abstract

Objective:Amyotrophic lateral sclerosis (ALS) progresses at different rates between patients, making clinical trial design difficult and dependent on large cohorts of patients. Currently, there are few data showing whether the left and right limbs progress at the same or different rates. This study addresses rates of decline in specific muscle groups of patients with ALS and assesses whether there is a relationship between left and right muscles in the same patient, regardless of overall progression.Methods:A large cohort of patients was used to assess decline in muscle strength in right and left limbs over time using 2 different methods: The Tufts Quantitative Neuromuscular Exam and Accurate Test of Limb Isometric Strength protocol. Then advanced linear regression statistical methods were applied to assess progression rates in each limb.Results:This report shows that linearized progression models can predict general slopes of decline with good accuracy. Critically, the data demonstrate that while overall decline is variable, there is a high degree of correlation between left and right muscle decline in ALS. This implies that irrespective of which muscle starts declining soonest or latest, their rates of decline following onset are more consistent.Conclusions:First, this study demonstrates a high degree of power when using unilateral treatment approaches to detect a slowing in disease progression in smaller groups of patients, thus allowing for paired statistical tests. These findings will be useful in transplantation trials that use muscle decline to track disease progression in ALS. Second, these findings discuss methods, such as tactical selection of muscle groups, which can improve the power efficiency of all ALS clinical trials.

Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial

“…The unilateral trial design allowed direct comparison of treated and untreated leg muscle strength, removing the variability in bilateral studies due to patient variability in strength decline. We have shown that muscle groups on each side of the body have remarkably similar progression rates in individual patients with ALS 39 . Therefore, we predicted that identical progression rates would indicate no treatment effect, whereas a slower decline in the treated leg compared with the untreated leg would suggest a positive graft effect.…”

“…ALS is a heterogeneous disease in which progression rates in individual patients can vary extensively 40 . However, we have shown in a large patient cohort that the progression rate in individual patients with ALS is remarkably similar for functional muscle groups on each side of the body 39 . Directly comparing treated and untreated legs for individual patients removes the variability seen in bilateral studies due to different progression rates.…”

Differential involvement of forearm muscles in ALS does not relate to sonographic structural nerve alterations

“…This apparent discrepancy may be related to the sample's relatively long disease duration (mean 3 years) as there is a high degree of left and right clinical muscle decline over the course of time (Rushton et al, 2017). In this instance, we refrained from the calculation of MRC scale inter-side differences, which seems to be not promising in long-standing disease (Rushton et al, 2017).…”

Intramuscular Injection of Bone Marrow Stem Cells in Amyotrophic Lateral Sclerosis Patients: A Randomized Clinical Trial

“…This ALS clinical trial design approach, based on comparing sides in the same patient, has recently been proposed by Rushton et al (2017) after demonstrating that progression rate in the left and right limb muscles of ALS sufferers shows a high degree of correlation; this progression is not related to the first muscle to begin declining and, on average, the right and left sides decline at the same rate following onset. For these reasons, an approach using one side for treatment and the other as a simultaneous internal control is perfectly feasible for stem cell transplant trials.…”