A post pandemic roadmap toward remote assessment for neuromuscular disorders: limitations and opportunities

Recent advances in technology and expanding therapeutic opportunities in neuromuscular disorders has resulted in greater interest in and development of remote assessments. Over the past year, the rapid and abrupt COVID-19 shutdowns and stay-at-home orders imposed challenges to routine clinical management and clinical trials. As in-person services were severely limited, clinicians turned to remote assessments through telehealth to allow for continued care. Typically, disease-specific clinical outcome assessments (COAs) for neuromuscular disorders (NMD) are developed over many years through rigorous and iterative processes to fully understand their psychometric properties. While efforts were underway towards developing remote assessments for NMD before the pandemic, few if any were fully developed or validated. These included assessments of strength, respiratory function and patient-reported outcomes, as well as wearable technology and other devices to quantify physical activity and function. Without many choices, clinicians modified COAs for a virtual environment recognizing it was not yet known how they compared to standard in-person administration. Despite being able to quickly adapt to the demands of the COVID-19 pandemic, these experiences with remote assessments uncovered limitations and opportunities. It became clear that existing COAs required modifications for use in a virtual environment limiting the interpretation of the information gathered. Still, the opportunity for real-world evaluation and reduced patient burden were clear benefits to remote assessment and may provide a more robust understanding and characterization of disease impact in NMD. Hence, we propose a roadmap navigating an informed post-pandemic path toward development and implementation of safe and successful use of remote assessments for patients with NMD

Consensus guidelines for improving quality of assessment and training for neuromuscular diseases

Critical components of successful evaluation of clinical outcome assessments (COAs) in multisite clinical trials and clinical practice are standardized training, administration, and documented reliability of scoring. Experiences of evaluators, alongside patient differences from regional standards of care, may contribute to heterogeneity in clinical center\u27s expertise. Achieving low variability and high reliability of COA is fundamental to clinical research and to give confidence in our ability to draw rational, interpretable conclusions from the data collected. The objective of this manuscript is to provide a framework to guide the learning process for COAs for use in clinics and clinical trials to maximize reliability and validity of COAs in neuromuscular disease (NMD). This is a consensus-based guideline with contributions from fourteen leading experts in clinical outcomes and the field of clinical outcome training in NMD. This framework should guide reliable and valid assessments in NMD specialty clinics and clinical trials. This consensus aims to expedite study start up with a progressive training pathway ranging from research naïve to highly experienced clinical evaluators. This document includes recommendations for education guidelines and roles and responsibilities of key stakeholders in COA assessment and implementation to ensure quality and consistency of outcome administration across different settings

The care of patients with Duchenne, Becker and other muscular dystrophies in the COVID-19 pandemic

The corona virus disease 2019 (COVID-19) pandemic has resulted in the reorganization of healthcare settings affecting clinical care delivery to patients with Duchenne and Becker muscular dystrophy (DBMD) as well as other inherited muscular dystrophies. The magnitude of the impact of this public health emergency on the care of patients with DBMD is unclear as they are suspected of having an increased risk for severe manifestations of COVID-19. In this paper, the authors discuss their consensus recommendations pertaining to care of these patients during the pandemic. We address issues surrounding corticosteroid and exon skipping treatments, cardiac medications, hydroxychloroquine use, emergency/respiratory care, rehabilitation management, and the conduct of clinical trials. We highlight the importance of collaborative treatment decisions between the patient, family, and health care provider, considering any geographic or institution-specific policies and precautions for COVID-19. We advocate for continuing multidisciplinary care for these patients using telehealth

Consensus-based care recommendations for adults with myotonic dystrophy type 1

Purpose of review Myotonic dystrophy type 1 (DM1) is a severe, progressive genetic disease that affects between 1 in 3,000 and 8,000 individuals globally. No evidence-based guideline exists to inform the care of these patients, and most do not have access to multidisciplinary care centers staffed by experienced professionals, creating a clinical care deficit. Recent findings The Myotonic Dystrophy Foundation (MDF) recruited 66 international clinicians experienced in DM1 patient care to develop consensus-based care recommendations. MDF created a 2-step methodology for the project using elements of the Single Text Procedure and the Nominal Group Technique. The process generated a 4-page Quick Reference Guide and a comprehensive, 55-page document that provides clinical care recommendations for 19 discrete body systems and/or care considerations. Summary The resulting recommendations are intended to help standardize and elevate care for this patient population and reduce variability in clinical trial and study environments. Described as “one of the more variable diseases found in medicine,” myotonic dystrophy type 1 (DM1) is an autosomal dominant, triplet-repeat expansion disorder that affects somewhere between 1:3,000 and 1:8,000 individuals worldwide.1 There is a modest association between increased repeat expansion and disease severity, as evidenced by the average age of onset and overall morbidity of the condition. An expansion of over 35 repeats typically indicates an unstable and expanding mutation. An expansion of 50 repeats or higher is consistent with a diagnosis of DM1. DM1 is a multisystem and heterogeneous disease characterized by distal weakness, atrophy, and myotonia, as well as symptoms in the heart, brain, gastrointestinal tract, endocrine, and respiratory systems. Symptoms may occur at any age. The severity of the condition varies widely among affected individuals, even among members of the same family. Comprehensive evidence-based guidelines do not currently exist to guide the treatment of DM1 patients. As a result, the international patient community reports varied levels of care and care quality, and difficulty accessing care adequate to manage their symptoms, unless they have access to multidisciplinary neuromuscular clinics. Consensus-based care recommendations can help standardize and improve the quality of care received by DM1 patients and assist clinicians who may not be familiar with the significant variability, range of symptoms, and severity of the disease. Care recommendations can also improve the landscape for clinical trial success by eliminating some of the inconsistencies in patient care to allow more accurate understanding of the benefit of potential therapies

Evaluation of Postural Control and Falls in Individuals with Myotonic Dystrophy Type 1

Thesis (Ph.D.)--University of Rochester. School of Nursing. Dept. of Health Practice Research, 2016.Purpose: Individuals with myotonic dystrophy report imbalance and falls. The purpose of this study was to assess postural control and examine its relationship with self-reported falls in individuals with myotonic dystrophy type 1 (DM1). Methods: In this prospective descriptive study, postural control was assessed at the body-structure function, activity, and patient reported level in 34 individuals with DM1. Body-structure function level assessment of postural control was performed using a body-worn inertial sensor to measure postural sway. Lower extremity strength and disease severity were also documented. The Timed Up and Go (TUG), Five Times Sit to Stand (FTSST), and the Mini-BESTest were performed as measures at the activity level and individuals completed the Activities-specific Balance Confidence Scale (ABC) as a patient reported measure of balance. Self-reported falls were collected using a fall history questionnaire as well as weekly contact for 12 weeks following their study visit. Test-retest reliability of the body-worn sensor, TUG, FTSST, Mini-BESTest, and ABC was performed on a subset of patients. Descriptive statistics were used to summarize the data. T-tests were used to analyze differences in postural sway parameters between individuals with DM1 and normative data. Spearman’s rank analysis was used to determine the relationship between variables. Logistic regression was used to explore which domain of postural control best predicts falls in individuals with DM1. Results: Sixty-two percent of individuals reported a fall during the 12 weeks following their baseline visit. Postural sway parameters in individuals with DM1 were significantly different from normative data. The postural sway parameter, root mean square, in the medial lateral plane, was associated with lower extremity strength (-0.394; p= 0.021), balance confidence (-0.359; p=0.037), and the Mini-BESTest (-0.437; p= 0.010). Test-retest reliability of the postural sway parameters (17/42), TUG, FTSST, Mini-BESTest, and ABC were determined to be adequate. None of the measures in this small sample were found to be significant predictors of falls. Conclusions: Postural sway measured using a body-worn sensor was able to differentiate between individuals with DM1 and normative data suggesting that postural sway may be a feasible way to measure balance impairment in individuals with DM1. Measures of postural sway are reliable and valid in individuals with DM1. However, these measures, along with other measures of postural control, were not significant predictors of falls in this study. Future studies involving larger samples and longer durations are needed to determine the sensitivity to change of postural control measures in individuals with DM1

Needs management in families affected by childhood-onset dystrophinopathies

Purpose: To collect information about the needs of families affected by childhood-onset dystrophinopathies residing in the United States. Methods: Individuals with an eligible dystrophinopathy were identified by the Muscular Dystrophy Surveillance, Tracking, and Research network. Between September 2008 and December 2012, 272 caregivers completed a 48-item survey about needs related to information, healthcare services, psychosocial issues, finances, caregiver demographics, and the individual’s functioning. Results: Overall, at least 80% of the survey items were identified as needs for more than one-half of caregivers. Among the needs identified, physical health and access to information were currently managed for most caregivers. Items identified as needed but managed less consistently were funding for needs not covered by insurance and psychosocial support. Conclusions: Healthcare providers, public health practitioners, and policymakers should be aware of the many needs reported by caregivers, and focus on addressing gaps in provision of needed financial and psychosocial services

Validity of the 6 minute walk test in facioscapulohumeral muscular dystrophy

INTRODUCTION: In preparation for future clinical trials, we determined the reliability, relationship to measures of disease severity, and consistency across sites of the 6 Minute Walk Test (6MWT) in patients with facioscapulohumeral muscular dystrophy (FSHD). METHODS: Genetically defined and clinically affected FSHD participants at 2 sites performed the 6MWT, the Timed Up and Go, and the 30 foot Go/Timed 10 meter test as measures of mobility using standard procedures. RESULTS: Eight-six participants representing the full range of severity performed the 6MWT. The mean 6MWT distance was 404.3 meters (SD 123.9), with no difference between sites. The 6MWT was reliable (n = 25; intraclass correlation coefficient = 0.99) and demonstrated moderate to strong correlations with lower extremity strength, functional outcomes, and FSHD Clinical Score. CONCLUSIONS: The 6MWT is reliable and is associated with other measures of FSHD disease severity. Future directions include assessing its sensitivity to disease progression.

Dose-Dependent Regulation of Alternative Splicing by MBNL Proteins Reveals Biomarkers for Myotonic Dystrophy

<div><p>Alternative splicing is a regulated process that results in expression of specific mRNA and protein isoforms. Alternative splicing factors determine the relative abundance of each isoform. Here we focus on MBNL1, a splicing factor misregulated in the disease myotonic dystrophy. By altering the concentration of MBNL1 in cells across a broad dynamic range, we show that different splicing events require different amounts of MBNL1 for half-maximal response, and respond more or less steeply to MBNL1. Motifs around MBNL1 exon 5 were studied to assess how <i>cis</i>-elements mediate the MBNL1 dose-dependent splicing response. A framework was developed to estimate MBNL concentration using splicing responses alone, validated in the cell-based model, and applied to myotonic dystrophy patient muscle. Using this framework, we evaluated the ability of individual and combinations of splicing events to predict functional MBNL concentration in human biopsies, as well as their performance as biomarkers to assay mild, moderate, and severe cases of DM.</p></div

Splicing events as biomarkers to measure functional MBNL concentration in DM1 muscle and response to therapeutics.

<p>(A) Ψ_min, Ψ_max, EC50, and slope, as well as [MBNL], were estimated for each splicing event and each sample, using 70% of the tibialis biopsies using a Bayesian inference framework. Sigmoid curves with 95% confidence intervals for <i>NFIX</i> and <i>CLASP1</i>, as estimated from 70% of the data, are shown, along with the Ψ values used to derive the curves (black points). Posterior distributions for [MBNL] were derived for 30% of the data (red points), and plotted for 3 specific samples (blue, green, and orange points). These distributions are also plotted on the right, along with the “gold standard” [MBNL] as estimated using 100% of the data (blue, green, and orange vertical lines). (B) The mean predictive power of each splicing event to predict “true” [MBNL] was calculated across 120 random subsets of training and test sets, where 70% of samples were used for training, and 30% for testing. Predictive power was defined as the posterior probability estimate at “true” [MBNL] assessed using all the data. The mean predictive power was computed separately across three patient subgroups–severe ([MBNL] < 0.33), moderate (0.33 < [MBNL] < 0.66), and mild ([MBNL] > 0.66) DM1, as well as across the entire patient cohort. Mean predictive power for each patient subgroup was plotted versus mean predictive power across the entire cohort, or all patients; splicing events that perform better in specific subgroups relative to the entire cohort are labeled. (C) The ability to estimate changes in [MBNL] depends on the splicing event used to infer [MBNL], as well as the disease severity at which treatment is initiated. Hypothetical changes in [MBNL] of +0.4 and +0.3 during a therapeutic trial are illustrated as purple and brown filled and outlined points, respectively in left panels. The posterior probability estimates of [MBNL] are illustrated in right panels. (D) A greater number of biomarkers can improve predictive power of estimates of [MBNL]. The posterior probability distribution for [MBNL] is shown when using 1, 2, 5, or 10 biomarkers for severely affected tibialis (top panel) or moderately affected tibialis (bottom panel). The value of [MBNL] obtained when using 100% of samples is shown as a dotted line; the posterior probability at this value of [MBNL] increases as the number of biomarkers increases. (E) Mean predictive power increases when using more biomarkers, up to a point. The best possible combination of biomarkers was chosen for each cross-validation trial, and predictive power was averaged across 120 cross-validation trials.</p

MBNL1 dose-responses.

<p>(A-G) Dose-response curves and splicing gels of individual events (A) <i>MBNL2</i> (B) <i>MBNL1</i> (C) <i>ATP2A1</i> (D) <i>CLASP1</i> (E) <i>FN1</i> (F) <i>INSR</i> (G) <i>NFIX</i>. Dox (ng/ml) was titrated to induce MBNL1 expression in HEK293 cells or treated with control siRNA or siRNA against MBNL1. siRNA treatment is not shown for events with transcripts that would be targeted by knock-down (MBNL1/2). RNA was isolated from the cells, RT-PCR was performed and DNA products were resolved on a native gel and isoform ratios quantified. Ψ values were plotted against the log(HA-MBNL1) treatment and fitted to a four-parameter dose-response curve. Splicing assays and western blots for MBNL1 protein quantification were performed in triplicate. (H) Curve fitting parameters are shown in the table.</p