by Megan Iammarino PT, DPT
Ann Neurol 2021 May;89(5):967-978.
Doi: 10.1002/ana.26044. Epub 2021 Feb 26.
Assessing Dysferlinopathy Patients Over Three Years With a New Motor Scale
Marni B Jacobs, Meredoith K James et al.
As various therapeutic strategies are currently in development for subtypes of limb girdle muscular dystrophy (LGMD), the goal of the Jain Clinical Outcome Study (COS), an international multicenter study, is to describe the natural history of dysferlinopathy (LGMDR2) and establish clinical trial readiness.
James and Jacobs et al. aim to document the development and responsiveness of the North Star assessment for limb girdle-type muscular dystrophies (NSAD) and to describe disease progression in dysferlinopathy over 3 years.
An analysis utilizing Rasch methodology examined 158 adapted-NSAA and 172 MFM-20 assessments from Year 1 of the Jain COS study, identified potential psychometric issues with each measurement scale including fit to construct, ceiling and floor effects, and redundant items. The authors found that despite a slight ceiling effect, the adapted-NSAA was better for measuring stronger individuals and the MFM-20 had items suitable for measuring more progressed, non-ambulant patients. The resultant new scale, the NSAD consists of all 22 a-NSAA items with the addition of 7 items from the MFM-20 with item scoring adapted to the results of the analysis. Items were reordered for efficiency in administration and to limit patient fatigue. The 29-item NSAD was then analyzed with the Rasch model, using assessment scores from Year 2 (N=153) and Year 3 (N=156) of the Jain COS study and the assessment was reported to have performed well. Authors report the NSAD measured a significant decline in performance with an average change of -1.73 points (p<0.0001, 95% CI: -2.33, -1.14), with an average change of -2.18 points and -0.64 points in Ambulant (N=87) and Non-Ambulant (N=36) patients, respectively. Inter-rater reliability was excellent with a reported ICC of 0.99.
The authors report a variety of meaningful trends, trajectories, and relationships between functional assessments to inform data-driven clinical trial inclusion criteria and sample size estimations. Evaluating disease progression over 3 full years, the early stage of disease onset was related to faster disease progression in this cohort, specifically those within 3 – 8 years since symptom onset. A 1-year placebo controlled clinical trial enrolling a stronger cohort, likely early in disease progression should plan to enroll 34 patients to measure a halt in disease progression. Similarly, the authors concluded that inclusion of performance criteria on timed functional measures (TUG and rise from floor velocity) may further lessen the number of patients needed to measure efficacy. However, while data-driven recommendations are important, they also need to be reasonable given the available population; authors report that using the most stringent inclusion criteria (i.e. 3-8 years since onset of symptoms, TUG <0.13 m/s, and rise from floor <0.21 m/s) would result in only 10 potentially eligible patients from the 14 site Jain COS study.
Meredith James, PT: Meredith James is a Clinical Specialist Neuromuscular Physiotherapist at the John Walton Centre for Muscular Dystrophy Research at Newcastle, where she is involved in clinical and research activity for children and adults with Neuromuscular disorders. Clinically, Meredith is responsible for the physiotherapy management of both children and adults with neuromuscular diseases. In particular, her interests are in assessment, orthotics, outcome measures and research into these areas. In her clinical research capacity, Meredith is responsible for the clinical evaluation of children and adults involved in natural history and clinical trials, as well as the development of clinically meaningful, reliable and sensitive outcome measures for NMD.
Marni Jacobs, PhD MPH: Dr. Marni Jacobs is an epidemiologist with over a decade of experience in both domestic and international research. She received her MPH with a concentration in Epidemiology from Columbia University Mailman School of Public Health, followed by a PhD in Public Health with an emphasis in Epidemiology from the University of California, San Diego in association with San Diego State University. Dr. Jacobs is interested in using epidemiological methods to design and analyze studies that can be used to predict disease course and inform clinical decision making to improve patient outcomes.
Megan Iammarino PT, DPT: Megan Iammarino is a research physical therapist at the Abigail Wexner Research Institute of Nationwide Children’s Hospital’s Center for Gene Therapy, specializing in the evaluation and care of patients with neuromuscular disease. Her research focus is the development, evaluation of, and administration of functional outcome measures. Other areas of interest include the study of innovative modalities to maximize functional benefits following therapeutic treatment and harnessing novel and existing technologies to measure the functional impact of movement disorders across the age span.
Published on 14 March 2022.
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This article is presented by the Publication Highlights Committee.